Seize the engine: Emerging cell cycle targets in breast cancer

Abstract

Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti-cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity. Advances in our understanding of the molecular basis of cell cycle disruption and the mechanisms of resistance to CDK4/6 inhibitors have reignited interest in blocking specific components of the cell cycle machinery, such as CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK. These targets play critical roles in regulating quiescence, DNA replication and chromosome segregation. Extensive preclinical data support their potential to overcome CDK4/6 inhibitor resistance, induce synthetic lethality or sensitise tumours to immune checkpoint inhibitors. This review provides a biological and drug development perspective on emerging cell cycle targets and novel inhibitors, many of which exhibit favourable safety profiles and promising activity in clinical trials.

Keywords

breast cancer / cell cycle checkpoints / clinical trials / cyclin-dependent kinases / drug development / mitotic kinases

References

[1] Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004;432(7015):316-323.

[2] Platet N, Cathiard AM, Gleizes M, Garcia M. Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol. 2004;51(1):55-67.

[3] Rinaldi J, Sokol ES, Hartmaier RJ, et al. The genomic landscape of metastatic breast cancer: insights from 11,000 tumors. PLoS One. 2020;15(5):e0231999.

[4] Razavi P, Chang MT, Xu G, et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell. 2018;34(3):427-438.e6.

[5] Shi Y, Jin J, Ji W, Guan X. Therapeutic landscape in mutational triple negative breast cancer. Mol Cancer. 2018;17(1):99.

[6] Jiang YZ, Ma D, Suo C, et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies. Cancer Cell. 2019;35(3):428-440.

[7] Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):l1.

[8] Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61-70.

[9] Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem. 1997;272(16):10882-10894.

[10] Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem. 1998;273(45):29864-29872.

[11] Herschkowitz JI, He X, Fan C, Perou CM. The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res. 2008;10(5):R75.

[12] Watt AC, Goel S. Cellular mechanisms underlying response and resistance to CDK4/6 inhibitors in the treatment of hormone receptor-positive breast cancer. Breast Cancer Res. 2022;24(1):17.

[13] Turner NC, Ro J, André F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209-219.

[14] Finn RS, Martin M, Rugo HS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-1936.

[15] Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-1748.

[16] Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, A phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218-5224.

[17] Sledge GW, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-2884.

[18] Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: mONALEESA-3. J Clin Oncol. 2018;36(24):2465-2472.

[19] Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. npj Breast Cancer. 2019;5(1):1-8.

[20] Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926-1936.

[21] Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316.

[22] Sledge GW, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial. JAMA Oncol. 2020;6(1):116-124.

[23] Cristofanilli M, Rugo HS, Im SA, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): updated analyses from PALOMA-3. J Clin Oncol. 2021;39(15):1000-1000.

[24] Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950.

[25] Xu B, Zhang Q, Zhang P, et al. Dalpiciclib or placebo plus fulvestrant in hormone receptor-positive and HER2-negative advanced breast cancer: a randomized, phase 3 trial. Nat Med. 2021;27(11):1904-1909.

[26] Xu B, Zhang QY, Zhang P, et al. LBA16 Dalpiciclib plus letrozole or anastrozole as first-line treatment for HR+/HER2- advanced breast cancer (DAWNA-2): a phase III trial. Ann Oncol. 2022;33:S1384-S1385.

[27] Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32(12):1571-1581.

[28] Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(17):LBA500-LBA500.

[29] Curigliano G, Gómez Pardo P, Meric-Bernstam F, et al. Ribociclib plus letrozole in early breast cancer: a presurgical, window-of-opportunity study. Breast. 2016;28:191-198.

[30] Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin Cancer Res. 2017;23(15):4055-4065.

[31] Cottu P, D'Hondt V, Dureau S, et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018;29(12):2334-2340.

[32] Johnston S, Puhalla S, Wheatley D, et al. Randomized phase II study evaluating palbociclib in addition to letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: pALLET Trial. J Clin Oncol. 2019;37(3):178-189.

[33] Khan QJ, O'Dea A, Bardia A, et al. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). J Clin Oncol. 2020;38(15):505-505.

[34] Hurvitz SA, Martin M, Press MF, et al. Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, Phase II neoadjuvant study in HR+/HER2- breast cancer. Clin Cancer Res. 2020;26(3):566-580.

[35] Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):33-43.

[36] Slamon DJ, Fasching PA, Patel R, et al. NATALEE: phase III study of ribociclib (RIBO) + endocrine therapy (ET) as adjuvant treatment in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (EBC). J Clin Oncol. 2019;37(15):TPS597-TPS597.

[37] Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2021;22(2):212-222.

[38] Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer. 2017;3(1):39-55.

[39] Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? npj Breast Cancer. 2019;5(1):1-9.

[40] O'Sullivan CC, Clarke R, Goetz MP, Robertson J. Cyclin-dependent kinase 4/6 inhibitors for treatment of hormone receptor-positive, ERBB2-negative breast cancer: a review. JAMA Oncol. 2023;9(9):1273-1282.

[41] Bulat I, Maglakelidze M, Krastev B, et al. 334P Lerociclib (G1T38), a continuously dosed oral CDK4/6 inhibitor, with fulvestrant in HR+/HER2- advanced breast cancer patients: updated phase II results and dose selection. Ann Oncol. 2020;31:S380.

[42] Tan AR, Wright GS, Thummala AR, et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 2019;20(11):1587-1601.

[43] O'Shaughnessy J, Wright GS, Thummala AR, et al. Abstract PD1-06: trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: final analysis of a randomized phase 2 trial. Cancer Res. 2021;81(4):PD1-PD06. Supplement.

[44] Lindeman GJ, Bowen R, Jerzak KJ, et al. Results from VERONICA: a randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC). J Clin Oncol. 2021;39(15):1004-1004.

[45] Bardia A, Neven P, Streich G, et al. Abstract GS2-02: elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator's choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: results of EMERALD phase 3 trial. Cancer Res. 2022;82(4):GS2-02.

[46] Hafner M, Mills CE, Subramanian K, et al. Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chemical Biology. 2019;26(8):1067-1080.e8.

[47] Wander SA, Han HS, Zangardi ML, et al. Clinical outcomes with abemaciclib after prior CDK4/6 inhibitor progression in breast cancer: a multicenter experience. J Natl Compr Canc Netw. 2021;24:1-8. Published online March.

[48] Kalinsky K, Accordino MK, Chiuzan C, et al. A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. J Clin Oncol. 2022;40(17):LBA1004-LBA1004.

[49] Mayer EL, Ren Y, Wagle N, et al. Abstract GS3-06: gS3-06 palbociclib after CDK4/6i and endocrine therapy (PACE): a randomized phase II study of fulvestrant, palbociclib, and avelumab for endocrine pre-treated ER+/HER2- metastatic breast cancer. Cancer Res. 2023;83(5):GS3-06.

[50] Álvarez-Fernández M, Malumbres M. Mechanisms of sensitivity and resistance to CDK4/6 inhibition. Cancer Cell. 2020;37(4):514-529.

[51] Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22(4):489-498.

[52] SABCS 2021 ePosters—A phase I/Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer. Accessed March 14, 2022.

[53] Juric D, Kalinsky K, Im SA, et al. INAVO121: phase III study of inavolisib (INAVO) + fulvestrant (FUL) vs. alpelisib (ALP) + FUL in patients (pts) with hormone receptor-positive, HER2-negative (HR+, HER2-) PIK3CA-mutated (mut) locally advanced or metastatic breast cancer (LA/mBC). J Clin Oncol. 2023;41(16):TPS1123-TPS1123.

[54] Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070.

[55] Cook MM, Al Rabadi L, Kaempf AJ, Saraceni MM, Savin MA, Mitri ZI. Everolimus plus exemestane treatment in patients with metastatic hormone receptor-positive breast cancer previously treated with CDK4/6 inhibitor therapy. Oncologist. 2021;26(2):101-106.

[56] Bardia A, Hurvitz SA, DeMichele A, et al. Phase I/II trial of exemestane, ribociclib, and everolimus in women with HR+/HER2− advanced breast cancer after progression on CDK4/6 inhibitors (TRINITI-1). Clin Cancer Res. 2021;27(15):4177-4185.

[57] SABCS 2021: SUMMIT Reveals Promise of Neratinib in HER2 Mutant Metastatic Breast Cancer. PracticeUpdate. Accessed March 14, 2022.

[58] Pernas S, Hernando C, Bermejo B, et al. Abstract OT2-20-01: rogaratinib, palbociclib and fulvestrant in advanced hormone receptor-positive (HR+), FGFR1/2-positive breast cancer: phase I trial plus an expansion cohort. Cancer Res. 2022;82(4):OT2-20-01.

[59] Malumbres M. Cyclin-dependent kinases. Genome Biol. 2014;15(6):122.

[60] Shapiro GI. Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clin Cancer Res. 2004;10(12):4270s-4275s. Pt 2.

[61] Tan AR, Yang X, Berman A, et al. Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer. Clin Cancer Res. 2004;10(15):5038-5047.

[62] Bible KC, Lensing JL, Nelson SA, et al. Phase 1 trial of flavopiridol combined with cisplatin or carboplatin in patients with advanced malignancies with the assessment of pharmacokinetic and pharmacodynamic end points. Clin Cancer Res. 2005;11(16):5935-5941.

[63] Diab S, Eckhardt S, Tan A, et al. A phase I study of R547, a novel, selective inhibitor of cell cycle and transcriptional cyclin dependent kinases (CDKs). J Clin Oncol. 2007;25(18):3528-3528.

[64] Massard C, Soria JC, Anthoney DA, et al. A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011;10(6):963-970.

[65] Keenan T, Liu D, Elmarakeby H, et al. Abstract CT050: expansion cohort of Phase I study of oral sapacitabine and oral seliciclib in patients with metastatic breast cancer and BRCA1/2 mutations. Cancer Res. 2019;79(13):CT050.

[66] Tolaney SM, Hilton JF, Cleary JM, et al. Phase I study of sapacitabine and seliciclib in patients with advanced solid tumors. J Clin Oncol. 2016;34(15):2503-2503.

[67] Mita MM, Joy AA, Mita A, et al. Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin Breast Cancer. 2014;14(3):169-176.

[68] Mitri Z, Karakas C, Wei C, et al. A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer. Invest New Drugs. 2015;33(4):890-894.

[69] Chien AJ, Gliwa AS, Rahmaputri S, et al. A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC) and response correlation with MYC-overexpression. J Clin Oncol. 2020;38(15):1076-1076.

[70] Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 2016;76(8):2301-2313.

[71] Pancholi S, Ribas R, Simigdala N, et al. Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities. Oncogene. 2020;39(25):4781-4797.

[72] Asghar US, Barr AR, Cutts R, et al. Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer. Clin Cancer Res. 2017;23(18):5561-5572.

[73] McDermott MSJ, Sharko AC, Munie J, et al. CDK7 inhibition is effective in all the subtypes of breast cancer: determinants of response and synergy with EGFR inhibition. Cells. 2020;9(3):E638.

[74] Pandey K, Park N, Park KS, et al. Combined CDK2 and CDK4/6 inhibition overcomes palbociclib resistance in breast cancer by enhancing senescence. Cancers (Basel). 2020;12(12):3566.

[75] Attia YM, Shouman SA, Salama SA, et al. Blockade of CDK7 reverses endocrine therapy resistance in breast cancer. Int J Mol Sci. 2020;21(8):2974.

[76] Guarducci C, Nardone A, Feiglin A, et al. Abstract PD7-12: inhibition of CDK7 overcomes resistance to CDK4/6 inhibitors in hormone receptor positive breast cancer cells. Cancer Res. 2019;79(4):PD7-PD12.

[77] Patel H, Periyasamy M, Sava GP, et al. ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment. Mol Cancer Ther. 2018;17(6):1156-1166.

[78] Yap TA, Basu C, Goldman JW, et al. Abstract P5-16-06: a first-in-human phase 1/2a dose escalation/expansion study of the first-in-class CDK2/4/6 inhibitor PF-06873600 alone or with endocrine therapy in patients with breast or ovarian cancer. Cancer Res. 2022;82(4):P5-16-06.

[79] Nuvation Bio Announces FDA Partial Clinical Hold for Phase 1 Study of NUV-422 in Solid Tumors. Accessed February 20, 2023.

[80] Yap TA, Elhaddad AM, Grisham RN, et al. First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer. J Clin Oncol. 2023;41(16):3010-3010.

[81] Patel MR, Juric D, Henick BS, et al. BLU-222, an oral, potent, and selective CDK2 inhibitor, in patients with advanced solid tumors: phase 1 monotherapy dose escalation. J Clin Oncol. 2023;41(16):3095-3095.

[82] Yap TA, Giordano A, Hamilton EP, et al. First-in-human first-in-class phase 1/2a study of the next generation CDK4-selective inhibitor PF-07220060 in patients (pts) with advanced solid tumors, enriched for HR+ HER2- mBC who progressed on prior CDK4/6 inhibitors and endocrine therapy. J Clin Oncol. 2023;41(16):3009-3009.

[83] Early Results from the Phase I Study of SY-1365, a Potent and Selective CDK7 inhibitor, in Patients with Ovarian Cancer and Advanced Solid Tumors | OncologyPRO. Accessed October 10, 2022.

[84] Sharma M, Bashir B, Hamilton E, et al. 518MO Tolerability and preliminary clinical activity of SY-5609, a highly potent and selective oral CDK7 inhibitor, in patients with advanced solid tumors. Ann Oncol. 2021;32:S587-S588.

[85] Juric D, Richardson DL, Bashir B, et al. Tolerability and preliminary activity of the potent, selective, oral CDK7 inhibitor SY-5609 in combination with fulvestrant in patients with advanced hormone receptor-positive (HR+), HER2- breast cancer (BC). J Clin Oncol. 2023;41(16):3081-3081.

[86] Howell SJ, Krebs MG, Lord S, et al. 265P Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR+BC). Ann Oncol. 2021;32:S477-S478.

[87] Howell SJ, Kenny LM, Lord S, et al. Abstract P1-18-10: a clinical study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced triple negative breast cancer (TNBC). Cancer Res. 2022;82(4):P1-18-10.

[88] Garralda E, Schram AM, Bedard PL, et al. A phase I dose-escalation study of LY3405105, a Covalent inhibitor of cyclin-dependent kinase 7, administered to patients with advanced solid tumors. Oncologist. Published online August 2, 2023:oyad215..

[89] SABCS 2022: A phase 1 study of the oral CDK7 inhibitor XL102 as a single agent and in combination therapy in patients With advanced solid tumors (QUARTZ-101): Initial results from the dose-escalation stage. Accessed February 28, 2023.

[90] Spear JM, Lu Z, Russu WA. Pharmacological inhibition of CDK8 in triple-negative breast cancer cell line MDA-MB-468 increases E2F1 protein, induces phosphorylation of STAT3 and apoptosis. Molecules. 2020;25(23):5728.

[91] Rzymski T, Gołas A, Mazan M, et al. Abstract P5-17-13: selective CDK8/CDK19 inhibitor RVU120 demonstrates efficacy against hormone-independent breast cancer cells in vitro and in vivo. Cancer Res. 2022;82(4):P5-17-13.

[92] Mack Z, Yastrebova M, Khamidullina A, et al. Abstract P4-01-17: preventing adaptive therapeutic resistance to CDK4/6 inhibition with CDK8/19 inhibitors. Cancer Res. 2022;82(4):P4-01-17.

[93] Saffran DC, Day MAL, Rioux N, et al. Abstract P5-08-05: preclinical activity of KB-0742, an oral, highly selective, CDK9 inhibitor, in cell lines and in MYC-high expressing, patient-derived models of multiple breast cancer subtypes. Cancer Res. 2022;82(4):P5-08-05.

[94] Smith HL, Southgate H, Tweddle DA, Curtin NJ. DNA damage checkpoint kinases in cancer. Expert Rev Mol Med. 2020;22:e2.

[95] Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66(6):801-817.

[96] Loncarek J, Bettencourt-Dias M. Building the right centriole for each cell type. J Cell Biol. 2018;217(3):823-835.

[97] Mason JM, Lin DCC, Wei X, et al. Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell. 2014;26(2):163-176.

[98] Marina M, Saavedra HI. Nek2 and Plk4: prognostic markers, drivers of breast tumorigenesis and drug resistance. Front Biosci (Landmark Ed). 2014;19:352-365.

[99] Kazazian K, Go C, Wu H, et al. Plk4 promotes cancer invasion and metastasis through Arp2/3 complex regulation of the actin cytoskeleton. Cancer Res. 2017;77(2):434-447.

[100] Brashavitskaya V(Olga), Kazazian K, Bagshaw R, et al. Abstract 2324: rhoGTPase-based regulation of cell motility by Plk4. Cancer Res. 2013;73(8):2324.

[101] Rosario CO, Ko MA, Haffani YZ, et al. Plk4 is required for cytokinesis and maintenance of chromosomal stability. Proc Natl Acad Sci USA. 2010;107(15):6888-6893.

[102] van de Vijver MJ, He YD, van ’t Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999-2009.

[103] Li Z, Dai K, Wang C, et al. Expression of polo-like kinase 4(PLK4) in breast cancer and its response to taxane-based neoadjuvant chemotherapy. J Cancer. 2016;7(9):1125-1132.

[104] Kahl I, Mense J, Finke C, et al. The cell cycle-related genes RHAMM, AURKA, TPX2, PLK1, and PLK4 are associated with the poor prognosis of breast cancer patients. J Cell Biochem. 2022;123(3):581-600.

[105] Parsyan A, Cruickshank J, Hodgson K, et al. Anticancer effects of radiation therapy combined with Polo-Like Kinase 4 (PLK4) inhibitor CFI-400945 in triple negative breast cancer. The Breast. 2021;58:6-9.

[106] Wong YL, Anzola JV, Davis RL, et al. Reversible centriole depletion with an inhibitor of Polo-like kinase 4. Science. 2015;348(6239):1155-1160.

[107] Suri A, Bailey AW, Tavares MT, et al. Evaluation of protein kinase inhibitors with PLK4 cross-over potential in a pre-clinical model of cancer. Int J Mol Sci. 2019;20(9):E2112.

[108] Lei Q, Xiong L, Xia Y, et al. YLT-11, a novel PLK4 inhibitor, inhibits human breast cancer growth via inducing maladjusted centriole duplication and mitotic defect. Cell Death Dis. 2018;9(11):1-14.

[109] Veitch ZW, Cescon DW, Denny T, et al. Safety and tolerability of CFI-400945, a first-in-class, selective PLK4 inhibitor in advanced solid tumours: a phase 1 dose-escalation trial. Br J Cancer. 2019;121(4):318-324.

[110] SABCS 2022: A phase II study of CFI-400945 in patients with advanced/metastatic cancer: Canadian Cancer Trials Group (CCTG) IND.237. Accessed February 20, 2023.

[111] SABCS 2022: CCTG IND.239: A phase 2 study of combined CFI-400945 and durvalumab in patients with advanced triple negative breast cancer (aTNBC). Accessed February 19, 2023.

[112] Matheson CJ, Backos DS, Reigan P. Targeting WEE1 kinase in cancer. Trends Pharmacol Sci. 2016;37(10):872-881.

[113] Nakajima H, Toyoshima-Morimoto F, Taniguchi E, Nishida E. Identification of a consensus motif for Plk (Polo-like kinase) phosphorylation reveals Myt1 as a Plk1 substrate. J Biol Chem. 2003;278(28):25277-25280.

[114] Watanabe Y, Uruha A, Suzuki S, et al. Clinical features and prognosis in anti-SRP and anti-HMGCR necrotising myopathy. J Neurol Neurosurg Psychiatry. 2016;87(10):1038-1044.

[115] Asquith CRM, Laitinen T, East MP. PKMYT1: a forgotten member of the WEE1 family. Nat Rev Drug Discov. 2020;19(3):157.

[116] Ghelli Luserna di Rorà A, Cerchione C, Martinelli G, Simonetti G. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target. J Hematol Oncol. 2020;13(1):126.

[117] de Nonneville A, Finetti P, Birnbaum D, Mamessier E, Bertucci F. WEE1 dependency and pejorative prognostic value in triple-negative breast cancer. Adv Sci. 2021;8(17):2101030.

[118] Fallah Y, Demas DM, Jin L, He W, Shajahan-Haq AN. Targeting WEE1 inhibits growth of breast cancer cells that are resistant to endocrine therapy and CDK4/6 inhibitors. Front Oncol. 2021;11:681530.

[119] Chen A, Kim BJ, Chan DW, et al. Abstract PD8-02: kinome profiling of ER+ breast cancer PDXs identifies PKMYT1 as a marker of hormone independent growth and poor outcome. Cancer Res. 2021;81(4):PD8-PD12.

[120] Iorns E, Lord CJ, Grigoriadis A, et al. Integrated functional, gene expression and genomic analysis for the identification of cancer targets. PLoS One. 2009;4(4):e5120.

[121] Murrow LM, Garimella SV, Jones TL, Caplen NJ, Lipkowitz S. Identification of WEE1 as a potential molecular target in cancer cells by RNAi screening of the human tyrosine kinome. Breast Cancer Res Treat. 2010;122(2):347-357.

[122] Panek RL, Lu GH, Klutchko SR, et al. In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. J Pharmacol Exp Ther. 1997;283(3):1433-1444.

[123] Palmer BD, Thompson AM, Booth RJ, et al. 4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution. J Med Chem. 2006;49(16):4896-4911.

[124] Chen X, Low KH, Alexander A, et al. Cyclin E overexpression sensitizes triple-negative breast cancer to wee1 kinase inhibition. Clin Cancer Res. 2018;24(24):6594-6610.

[125] Ha DH, Min A, Kim S, et al. Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer. Sci Rep. 2020;10(1):9930.

[126] Jin J, Fang H, Yang F, et al. Combined inhibition of ATR and WEE1 as a novel therapeutic strategy in triple-negative breast cancer. Neoplasia. 2018;20(5):478-488.

[127] Martin LA, Pancholi S, Ribas R, et al. Abstract P3-03-09: resistance to palbociclib depends on multiple targetable mechanisms highlighting the potential of drug holidays and drug switching to improve therapeutic outcome. Cancer Res. 2017;77(4):P3-03-09.

[128] Do K, Wilsker D, Ji J, et al. Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol. 2015;33(30):3409-3415.

[129] Leijen S, van Geel RMJM, Pavlick AC, et al. Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. J Clin Oncol. 2016;34(36):4371-4380.

[130] Tutt A, Tovey H, Cheang MCU, et al. A randomised phase III trial of carboplatin compared with docetaxel in BRCA1/2 mutated and pre-specified triple negative breast cancer “BRCAness” subgroups: the TNT Trial. Nat Med. 2018;24(5):628-637.

[131] Isakoff SJ, Mayer EL, He L, et al. TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol. 2015;33(17):1902-1909.

[132] Keenan TE, Li T, Vallius T, et al. Clinical efficacy and molecular response correlates of the WEE1 inhibitor adavosertib combined with cisplatin in patients with metastatic triple-negative breast cancer. Clin Cancer Res. 2021;27(4):983-991.

[133] Takebe N, Naqash AR, O'Sullivan Coyne G, et al. Safety, antitumor activity, and biomarker analysis in a phase i trial of the once-daily wee1 inhibitor adavosertib (AZD1775) in patients with advanced solid tumors. Clin Cancer Res. 2021;27(14):3834-3844.

[134] Tutt A, Stephens C, Frewer P, et al. VIOLETTE: a randomized phase II study to assess the DNA damage response inhibitors AZD6738 or AZD1775 in combination with olaparib (Ola) versus Ola monotherapy in patients (pts) with metastatic, triple-negative breast cancer (TNBC). J Clin Oncol. 2019;37(15):TPS1112-TPS1112.

[135] Moore KN, Chambers SK, Hamilton EP, et al. Adavosertib with chemotherapy in patients with primary platinum-resistant ovarian, fallopian tube, or peritoneal cancer: an open-label, four-arm, phase II study. Clin Cancer Res. 2022;28(1):36-44.

[136] Lin CC, Grewal J, Sommerhalder D, et al. 482P Safety, pharmacokinetic (PK), and pharmacodynamic profiles of the WEE1 inhibitor IMP7068 in patients (pts) with advanced solid tumors. Ann Oncol. 2022;33:S760-S761.

[137] Tolcher A, Mamdani H, Chalasani P, et al. Abstract CT016: clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 dose-escalation trial in patients with advanced solid tumors. Cancer Res. 2021;81(13):CT016.

[138] O'Dowd C, Gavory G, Burkamp F, et al. Abstract 4423: antitumor activity of the novel oral highly selective Wee1 inhibitor Debio 0123. Cancer Res. 2019;79(13):4423.

[139] Gelderblom H, Gietema JA, Desar IME, et al. 601TiP First-in-human phase I study of a novel oral Wee1 inhibitor (Debio 0123) in combination with carboplatin in patients with advanced solid tumours. Ann Oncol. 2020;31:S501-S502.

[140] Gelderblom H, Jalving M, Desar I, et al. Debio 0123-101: a phase 1 trial of Debio 0123 in combination with carboplatin in advanced solid tumors—Safety, pharmacokinetic, and preliminary antitumor activity data. J Clin Oncol. 2023;41(16):3012-3012.

[141] Gallo D, Young JTF, Fourtounis J, et al. CCNE1 amplification is synthetic lethal with PKMYT1 kinase inhibition. Nature. 2022;604(7907):749-756.

[142] Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74-88.

[143] Mou PK, Yang EJ, Shi C, Ren G, Tao S, Shim JS. Aurora kinase A, a synthetic lethal target for precision cancer medicine. Exp Mol Med. 2021;53(5):835-847.

[144] Siggelkow W, Boehm D, Gebhard S, et al. Expression of aurora kinase A is associated with metastasis-free survival in node-negative breast cancer patients. BMC Cancer. 2012;12:562.

[145] Xu J, Wu X, Zhou Wha, et al. Aurora-A identifies early recurrence and poor prognosis and promises a potential therapeutic target in triple negative breast cancer. PLoS One. 2013;8(2):e56919.

[146] Thrane S, Pedersen AM, Thomsen MBH, et al. A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells. Oncogene. 2015;34(32):4199-4210.

[147] Opyrchal M, Salisbury JL, Zhang S, et al. Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells. PLoS One. 2014;9(5):e96995.

[148] Zheng XQ, Guo JP, Yang H, et al. Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα in breast cancer. Oncogene. 2014;33(42):4985-4996.

[149] Hole S, Pedersen AM, Lykkesfeldt AE, Yde CW. Aurora kinase A and B as new treatment targets in aromatase inhibitor-resistant breast cancer cells. Breast Cancer Res Treat. 2015;149(3):715-726.

[150] Wander SA, Cohen O, Gong X, et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor-positive metastatic breast cancer. Cancer Discov. 2020;10(8):1174-1193.

[151] Gong X, Du J, Parsons SH, et al. Aurora A kinase inhibition is synthetic lethal with loss of the RB1 tumor suppressor gene. Cancer Discov. 2019;9(2):248-263.

[152] Hoar K, Chakravarty A, Rabino C, et al. MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol. 2007;27(12):4513-4525.

[153] Marumoto T, Hirota T, Morisaki T, et al. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells. 2002;7(11):1173-1182.

[154] Huck JJ, Zhang M, Mettetal J, et al. Translational exposure-efficacy modeling to optimize the dose and schedule of taxanes combined with the investigational Aurora A kinase inhibitor MLN8237 (alisertib). Mol Cancer Ther. 2014;13(9):2170-2183.

[155] Soria-Bretones I, Thu KL, Silvester J, et al. The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with mitotic aberrations. Sci Adv. 2022;8(36):eabq4293.

[156] Novais P, Silva PMA, Amorim I, Bousbaa H. Second-generation antimitotics in cancer clinical trials. Pharmaceutics. 2021;13(7):1011.

[157] Du R, Huang C, Liu K, Li X, Dong Z. Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy. Mol Cancer. 2021;20(1):15.

[158] Haddad TC, D'Assoro A, Suman V, et al. Phase I trial to evaluate the addition of alisertib to fulvestrant in women with endocrine-resistant, ER+ metastatic breast cancer. Breast Cancer Res Treat. 2018;168(3):639-647.

[159] Haddad T, D'Assoro A, Suman V, et al. Abstract PD2-05: randomized phaseII trial to evaluate alisertib alone or combined with fulvestrant for advanced, endocrine-resistant breast cancer (TBCRC 041). Cancer Res. 2021;81(4):PD2-05.

[160] O'Shaughnessy J, McIntyre K, Wilks S, et al. Efficacy and safety of weekly paclitaxel with or without oral alisertib in patients with metastatic breast cancer: a randomized clinical trial. JAMA Netw Open. 2021;4(4):e214103.

[161] Melichar B, Adenis A, Lockhart AC, et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol. 2015;16(4):395-405.

[162] Haddad TC, Suman VJ, D'Assoro AB, et al. Evaluation of alisertib alone or combined with fulvestrant in patients with endocrine-resistant advanced breast cancer: the phase 2 TBCRC041 randomized clinical trial. JAMA Oncol.

[163] Zhang X, Wei C, Liang H, Han L. Polo-like kinase 4's critical role in cancer development and strategies for Plk4-targeted therapy. Front Oncol. 2021;11:587554.

[164] Asteriti IA, De Mattia F, Guarguaglini G. Cross-Talk between AURKA and Plk1 in mitotic entry and spindle assembly. Front Oncol. 2015;5.

[165] Zou J, Rezvani K, Wang H, Lee KS, Zhang D. BRCA1 downregulates the kinase activity of Polo-like kinase 1 in response to replication stress. Cell Cycle. 2013;12(14):2255-2265.

[166] Benada J, Burdová K, Lidak T, von Morgen P, Macurek L. Polo-like kinase 1 inhibits DNA damage response during mitosis. Cell Cycle. 2015;14(2):219-231.

[167] Wierer M, Verde G, Pisano P, et al. PLK1 signaling in breast cancer cells cooperates with estrogen receptor-dependent gene transcription. Cell Rep. 2013;3(6):2021-2032.

[168] Ueda A, Oikawa K, Fujita K, et al. Therapeutic potential of PLK1 inhibition in triple-negative breast cancer. Lab Invest. 2019;99(9):1275-1286.

[169] Montaudon E, Nikitorowicz-Buniak J, Sourd L, et al. PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance. Nat Commun. 2020;11(1):4053.

[170] Gutteridge REA, Ndiaye MA, Liu X, Ahmad N. Plk1 inhibitors in cancer therapy: from laboratory to clinics. Mol Cancer Ther. 2016;15(7):1427-1435.

[171] Lin CC, Su WC, Yen CJ, et al. A phase I study of two dosing schedules of volasertib (BI 6727), an intravenous polo-like kinase inhibitor, in patients with advanced solid malignancies. Br J Cancer. 2014;110(10):2434-2440.

[172] Awada A, Dumez H, Aftimos PG, et al. Phase I trial of volasertib, a Polo-like kinase inhibitor, plus platinum agents in solid tumors: safety, pharmacokinetics and activity. Invest New Drugs. 2015;33(3):611-620.

[173] de Braud F, Cascinu S, Spitaleri G, et al. A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors. Ann Oncol. 2015;26(11):2341-2346.

[174] Machiels JP, Peeters M, Herremans C, et al. A phase I study of volasertib combined with afatinib, in advanced solid tumors. Cancer Chemother Pharmacol. 2015;76(4):843-851.

[175] Ohnuma T, Lehrer D, Ren C, et al. Phase 1 study of intravenous rigosertib (ON 01910.Na), a novel benzyl styryl sulfone structure producing G2/M arrest and apoptosis, in adult patients with advanced cancer. Am J Cancer Res. 2013;3(3):323-338.

[176] Ma WW, Messersmith WA, Dy GK, et al. Phase I study of rigosertib, an inhibitor of the phosphatidylinositol 3-kinase and Polo-like kinase 1 pathways, combined with gemcitabine in patients with solid tumors and pancreatic cancer. Clin Cancer Res. 2012;18(7):2048-2055.

[177] Barnum KJ, O'Connell MJ. Cell cycle regulation by checkpoints. Methods Mol Biol. 2014;1170:29-40.

[178] Lawrence KS, Engebrecht J. The spindle assembly checkpoint: more than just keeping track of the spindle. Trends Cell Mol Biol. 2015;10:141-150.

[179] Abrieu A, Magnaghi-Jaulin L, Kahana JA, et al. Mps1 is a kinetochore-associated kinase essential for the vertebrate mitotic checkpoint. Cell. 2001;106(1):83-93.

[180] Daniel J, Coulter J, Woo JH, Wilsbach K, Gabrielson E. High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells. Proc Natl Acad Sci USA. 2011;108(13):5384-5389.

[181] Yuan B, Xu Y, Woo JH, et al. Increased expression of mitotic checkpoint genes in breast cancer cells with chromosomal instability. Clin Cancer Res. 2006;12(2):405-410.

[182] Maire V, Baldeyron C, Richardson M, et al. TTK/hMPS1 is an attractive therapeutic target for triple-negative breast cancer. PLoS One. 2013;8(5):e63712.

[183] Maia ARR, de Man J, Boon U, et al. Inhibition of the spindle assembly checkpoint kinase TTK enhances the efficacy of docetaxel in a triple-negative breast cancer model. Ann Oncol. 2015;26(10):2180-2192.

[184] Thu KL, Silvester J, Elliott MJ, et al. Disruption of the anaphase-promoting complex confers resistance to TTK inhibitors in triple-negative breast cancer. Proc Natl Acad Sci USA. 2018;115(7):E1570-E1577.

[185] Elango R, Vishnubalaji R, Shaath H, Alajez NM. Molecular subtyping and functional validation of TTK, TPX2, UBE2C, and LRP8 in sensitivity of TNBC to paclitaxel. Mol Ther Methods Clin Dev. 2021;20:601-614.

[186] Gao YH, Qu SS, Cao LQ, Yao M. TTK predicts triple positive breast cancer prognosis and regulates tumor proliferation and invasion. Neoplasma:210421N541. Published online.

[187] Schmidt M, Budirahardja Y, Klompmaker R, Medema RH. Ablation of the spindle assembly checkpoint by a compound targeting Mps1. EMBO Rep. 2005;6(9):866-872.

[188] Santaguida S, Tighe A, D'Alise AM, Taylor SS, Musacchio A. Dissecting the role of MPS1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibitor reversine. J Cell Biol. 2010;190(1):73-87.

[189] Martinez R, Blasina A, Hallin JF, et al. Mitotic checkpoint kinase Mps1 has a role in normal physiology which impacts clinical utility. PLoS One. 2015;10(9):e0138616.

[190] Lorusso P, Chawla SP, Bendell J, et al. First-in-human study of the monopolar spindle 1 (Mps1) kinase inhibitor BAY 1161909 in combination with paclitaxel in subjects with advanced malignancies. Ann Oncol. 2018;29:viii138.

[191] Atrafi F, Boix O, Subbiah V, et al. A Phase I study of an MPS1 inhibitor (BAY 1217389) in combination with paclitaxel using a novel randomized continual reassessment method for dose escalation. Clin Cancer Res. 2021;27(23):6366-6375.

[192] Mason JM, Wei X, Fletcher GC, et al. Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. Proc Natl Acad Sci USA. 2017;114(12):3127-3132.

[193] Bretones IS, Thu KL, Silvester J, et al. Abstract PD2-03: cDK4/6 inhibitor-resistant ER+ breast cancer cell lines are hypersensitive to TTK inhibition. Cancer Res. 2020;80(4):PD2-PD2-03. Supplement.

[194] SABCS 2022: An update to a Phase I trial of CFI-402257, an oral TTK inhibitor, in patients with advanced solid tumors with HER2-negative breast cancer expansion cohorts. Accessed February 20, 2023.

[195] Mates M, Bedard P, Hilton J, et al. 38MO IND.236: a Canadian Cancer Trial Group (CCTG) phase Ib trial of combined CFI-402257 and weekly paclitaxel (Px) in patients with HER2-negative (HER2-) advanced breast cancer (BC). Ann Oncol. 2021;32:S16.

[196] Bedard P, Mates M, Gelmon KA, et al. 19O A phase Ib trial of CFI-402257 in combination with weekly paclitaxel in patients with advanced HER2-negative (HER2-) breast cancer (aBC). Ann Oncol. 2020;31:S7.

[197] Schöffski P, Awada A, de la Bigne AM, et al. First-in-man, first-in-class phase I study with the monopolar spindle 1 kinase inhibitor S81694 administered intravenously in adult patients with advanced, metastatic solid tumours. Eur J Cancer. 2022;169:135-145.

[198] Cohen-Sharir Y, McFarland JM, Abdusamad M, et al. Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition. Nature. 2021;590(7846):486-491.

[199] Marquis C, Fonseca CL, Queen KA, et al. Chromosomally unstable tumor cells specifically require KIF18A for proliferation. Nat Commun. 2021;12(1):1213.

[200] Belmontes B, Moriguchi J, Chung G, et al. Abstract 516: discovery and preclinical characterization of AMG 650, a first-in-class inhibitor of kinesin KIF18A motor protein with potent activity against chromosomally unstable cancers. Cancer Res. 2023;83(7):516.

[201] Zhang C, Zhu C, Chen H, et al. Kif18A is involved in human breast carcinogenesis. Carcinogenesis. 2010;31(9):1676-1684.

[202] Govindan R, Townsend AR, Miller KD, et al. Trial in progress: a phase 1, multicenter, open-label, dose-exploration and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and efficacy of AMG650 in subjects with advanced solid tumors. J Clin Oncol. 2021;39(15):TPS5600-TPS5600.

[203] Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. Published online May 18, 2022:JCO.22.00338..

[204] Bidard FC, Hardy-Bessard AC, Dalenc F, et al. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2022;23(11):1367-1377.

[205] Cristofanilli M, Rugo HS, Im SA, et al. Overall survival with palbociclib and fulvestrant in women with HR+/HER2- ABC: updated exploratory analyses of PALOMA-3, a double-blind, phase III randomized study. Clin Cancer Res. 2022;28(16):3433-3442.

[206] Tolaney SM, Toi M, Neven P, et al. Clinical significance of PIK3CA and ESR1 mutations in circulating tumor DNA: analysis from the MONARCH 2 study of abemaciclib plus fulvestrant. Clin Cancer Res. 2022;28(8):1500-1506.

[207] Bardia A, Su F, Solovieff N, et al. Genomic profiling of premenopausal HR+ and HER2- metastatic breast cancer by circulating tumor DNA and association of genetic alterations with therapeutic response to endocrine therapy and ribociclib. JCO Precis Oncol. 2021(5):1408-1420.

[208] Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533.

[209] Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763.

[210] Safonov A, Bandlamudi C, de Lara PT, et al. Abstract GS4-08: comprehensive genomic profiling of patients with breast cancer identifies germline-somatic interactions mediating therapy resistance. Cancer Res. 2022;82(4):GS4-08.

[211] Fuentes Antrás J, El Ghamrasni S, Zou J, et al. Impact of pathogenic germline BRCA1/2 and PALB2 mutations and tumor aneuploidy in patients with HR+/HER2- metastatic breast cancer treated with CDK4/6 inhibitors. J Clin Oncol. 2023;41(16):1075-1075.

[212] Bruno L, Ostinelli A, Waisberg F, et al. Cyclin-Dependent kinase 4/6 inhibitor outcomes in patients with advanced breast cancer carrying germline pathogenic variants in DNA repair-related genes. JCO Precis Oncol. 2022;6:e2100140.

[213] Collins JM, Nordstrom BL, McLaurin KK, et al. A real-world evidence study of CDK4/6 inhibitor treatment patterns and outcomes in metastatic breast cancer by germline BRCA mutation status. Oncol Ther. 2021;9(2):575-589.

[214] Suzuki Y, Wenwen W, Ohta T, Hayashi SI. Molecular targeted drugs resistance impairs double-strand break repair and sensitizes ER-positive breast cancer to PARP inhibitors. Breast Cancer. 2021. Published o.

[215] Park YH, Im SA, Park K, et al. Prospective longitudinal multi-omics study of palbociclib resistance in hormone receptor+/HER2- metastatic breast cancer. J Clin Oncol. 2021;39(15):1013-1013.

[216] Li S, Zhang Y, Wang N, et al. Pan-cancer analysis reveals synergistic effects of CDK4/6i and PARPi combination treatment in RB-proficient and RB-deficient breast cancer cells. Cell Death Dis. 2020;11(4):1-16.

[217] Zhu X, Chen L, Huang B, et al. Efficacy and mechanism of the combination of PARP and CDK4/6 inhibitors in the treatment of triple-negative breast cancer. J Exp Clin Cancer Res. 2021;40(1):122.

[218] Simoneau A, Xiong R, Zou L. The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells. Genes Dev. 2021;35(17-18):1271-1289.

[219] Tutt A, Nowecki Z, Szoszkiewicz R, et al. 161O VIOLETTE: randomised phase II study of olaparib (ola) + ceralasertib (cer) or adavosertib (ada) vs ola alone in patients (pts) with metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2022;33:S194-S195.

[220] Telli ML, Tolaney SM, Shapiro GI, et al. Phase 1b study of berzosertib and cisplatin in patients with advanced triple-negative breast cancer. npj Breast Cancer. 2022;8(1):1-9.

[221] Middleton MR, Dean E, Evans TRJ, et al. Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours. Br J Cancer. 2021;125(4):510-519.

[222] Krebs MG, Lopez J, El-Khoueiry A, et al. Abstract CT026: phase I study of AZD6738, an inhibitor of ataxia telangiectasia Rad3-related (ATR), in combination with olaparib or durvalumab in patients (pts) with advanced solid cancers. Cancer Res. 2018;78(13):CT026.

[223] Bukhari AB, Lewis CW, Pearce JJ, Luong D, Chan GK, Gamper AM. Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis. J Clin Invest. 2019;129(3):1329-1344.

[224] Lamballe F, Ahmad F, Vinik Y, et al. Modeling heterogeneity of triple-negative breast cancer uncovers a novel combinatorial treatment overcoming primary drug resistance. Adv Sci (Weinh). 2020;8(3):2003049.

[225] Lewis CW, Bukhari AB, Xiao EJ, et al. Upregulation of Myt1 promotes acquired resistance of cancer cells to Wee1 inhibition. Cancer Res. 2019;79(23):5971-5985.

[226] Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471-475.

[227] Da S, Rp B, Ja D, et al. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep. 2018;22(11).

[228] Deng J, Wang ES, Jenkins RW, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018;8(2):216-233.

[229] Yuan Y, Lee JS, Yost SE, et al. Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer. Eur J Cancer. 2021;154:11-20.

[230] Rugo HS, Kabos P, Beck JT, et al. Abemaciclib in combination with pembrolizumab for HR+, HER2− metastatic breast cancer: phase 1b study. npj Breast Cancer. 2022;8(1):1-8.

[231] Herold CI, Trippa L, Li T, et al. Abstract P3-14-03: a phase 1b study of the CDK4/6 inhibitor ribociclib in combination with the PD-1 inhibitor spartalizumab in patients with hormone receptor-positive metastatic breast cancer (HR+ MBC) and metastatic ovarian cancer (MOC). Cancer Res. 2020;80(4):P3-14-03.

[232] Reda M, Ngamcherdtrakul W, Nelson MA, et al. Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment. Nat Commun. 2022;13(1):4261.

[233] Taniguchi H, Caeser R, Chavan SS, et al. WEE1 inhibition enhances the antitumor immune response to PD-L1 blockade by the concomitant activation of STING and STAT1 pathways in SCLC. Cell Rep. 2022;39(7):110814.

[234] Kitajima S, Tani T, Springer BF, et al. MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer. Cancer Cell. 2022;40(10):1128-1144.

[235] Do KT, Frej K, Bhushan K, et al. Phase 1 safety, pharmacokinetic and pharmacodynamic study of fadraciclib (CYC065), a cyclin dependent kinase inhibitor, in patients with advanced cancers (NCT02552953). Eur J Cancer. 2020;138:S7.

[236] Krebs MG, Lord S, Kenny L, et al. 230MO First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies. Ann Oncol. 2021;32:S458.

[237] SABCS 2021 ePosters—A clinical study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced triple negative breast cancer (TNBC). Accessed February 4, 2022.

[238] Cescon DW, Hansen AR, Abdul Razak AR, et al. Phase I study of CFI-402257, an oral TTK inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2017;35(15):TPS2619-TPS2619.

[239] Hilton J, Renouf DJ, Cescon DW, et al. Abstract P1-18-17: phase I study of cfi-402257, an oral ttk inhibitor, in patients with advanced solid tumors with breast cancer expansion cohorts. Cancer Res. 2022;82(4):P1-18-17.

[240] SABCS 2022: CCTG IND.236: A Phase 1b trial of combined CFI-402257 and weekly paclitaxel in patients with HER2-negative (HER2-) advanced breast cancer (aBC). Accessed February 20, 2023.

[241] Weiss GJ, Jameson G, Von Hoff DD, et al. Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors. Invest New Drugs. 2018;36(1):85-95.

[242] Mross K, Frost A, Steinbild S, et al. Phase I dose escalation and pharmacokinetic study of BI 2536, a novel Polo-like kinase 1 inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2008;26(34):5511-5517.

[243] Doi T, Murakami H, Wan K, et al. A first-in-human phase I dose-escalation study of MK-1496, first-in-class orally available novel PLK1 inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2011;29(15):3012-3012.

[244] Falchook G, Kurzrock R, Gouw L, et al. Investigational Aurora A kinase inhibitor alisertib (MLN8237) as an enteric-coated tablet formulation in non-hematologic malignancies: phase 1 dose-escalation study. Invest New Drugs. 2014;32(6):1181-1187.

[245] Dees EC, Cohen RB, von Mehren M, et al. Phase I study of aurora A kinase inhibitor MLN8237 in advanced solid tumors: safety, pharmacokinetics, pharmacodynamics, and bioavailability of two oral formulations. Clin Cancer Res. 2012;18(17):4775-4784.

[246] Cervantes A, Elez E, Roda D, et al. Phase I pharmacokinetic/pharmacodynamic study of MLN8237, an investigational, oral, selective aurora A kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012;18(17):4764-4774.

[247] Shah HA, Fischer JH, Venepalli NK, et al. Phase I study of aurora A kinase inhibitor alisertib (MLN8237) in combination with selective VEGFR inhibitor pazopanib for therapy of advanced solid tumors. Am J Clin Oncol. 2019;42(5):413-420.

[248] Sarantopoulos J, Hahn NM, Higano CS, et al. Phase I trial of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in combination with docetaxel (DTX) in patients (pts) with advanced solid tumors, including castration-resistant prostate cancer (CRPC). J Clin Oncol. 2014;32(4):217-217.

[249] Dees EC, Infante JR, Cohen RB, et al. Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011;67(4):945-954.

[250] Chu Q, Bouganim N, Fortier C, et al. Abstract CT083: a Phase I/II study of aurora kinase A inhibitor, LY3295668 erbumine (AK-01): safety as monotherapy in patients with locally advanced or metastatic solid tumors. Cancer Res. 2019;79(13):CT083.

[251] Robbrecht D, Eskens F, Calvo E, et al. First-in-human phase I and pharmacological study of TAS-119, a selective Aurora A (AurA) kinase inhibitor, in patients (pts) with advanced solid tumors. J Clin Oncol. 2019;37(15):3063-3063.

[252] Cardin DB, Park H, Diamond JR, et al. Phase I study of the Aurora A kinase (AurA) inhibitor TAS-119 with paclitaxel (P) in advanced solid tumors. J Clin Oncol. 2019;37(15):3031-3031.

[253] McNeish I, Anthoney A, Loadman P, et al. A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora kinase inhibitor GSK1070916A. J Clin Oncol. 2013;31(15):2525-2525.

[254] Sun Y, Yang L, Hao X, et al. Phase I dose-escalation study of chiauranib, a novel angiogenic, mitotic, and chronic inflammation inhibitor, in patients with advanced solid tumors. J Hematol Oncol. 2019;12(1):9.

[255] Schwartz GK, Carvajal RD, Midgley R, et al. Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Invest New Drugs. 2013;31(2):370-380.

[256] Carducci M, Shaheen M, Markman B, et al. A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors. Invest New Drugs. 2018;36(6):1060-1071.

[257] Burris HA, Jones SF, Williams DD, et al. A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors. Invest New Drugs. 2011;29(3):467-472.

[258] Jones SF, Plummer ER, Burris HA, et al. Phase I study of ispinesib in combination with carboplatin in patients with advanced solid tumors. J Clin Oncol. 2006;24(18):2027-2027.

[259] Blagden SP, Molife LR, Seebaran A, et al. A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer. 2008;98(5):894-899.

[260] Gomez HL, Philco M, Pimentel P, et al. Phase I dose-escalation and pharmacokinetic study of ispinesib, a kinesin spindle protein inhibitor, administered on days 1 and 15 of a 28-day schedule in patients with no prior treatment for advanced breast cancer. Anticancer Drugs. 2012;23(3):335-341.

[261] Dent SF, Gelmon KA, Chi KN, et al. NCIC CTG IND.181: phase I study of AT9283 given as a weekly 24 hour infusion in advanced malignancies. Invest New Drugs. 2013;31(6):1522-1529.

[262] Traynor AM, Hewitt M, Liu G, et al. Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol. 2011;67(2):305-314.

[263] Schöffski P, Jones SF, Dumez H, et al. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours. Eur J Cancer. 2011;47(15):2256-2264.

[264] Robert F, Verschraegen C, Hurwitz H, et al. A phase I trial of sns-314, a novel and selective pan-aurora kinase inhibitor, in advanced solid tumor patients. J Clin Oncol. 2009;27(15):2536-2536.

[265] Mita M, Gordon M, Rejeb N, et al. A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors. Target Oncol. 2014;9(3):215-224.

[266] Diamond JR, Bastos BR, Hansen RJ, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of ENMD-2076, a novel angiogenic and Aurora kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2011;17(4):849-860.

[267] Diamond JR, Eckhardt SG, Pitts TM, et al. A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer. Breast Cancer Res. 2018;20(1):82.

[268] Maitland ML, Piha-Paul S, Falchook G, et al. Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial. Br J Cancer. 2018;118(8):1042-1050.

RIGHTS & PERMISSIONS

2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.