Protein tyrosine phosphatases: emerging role in cancer therapy resistance

Abstract

Background: Tyrosine phosphorylation of intracellular proteins is a post-translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross-talk between signaling pathways. In the context of cancer, PTP-mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth-stimulatory signaling pathways or modulation of the immune-suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy.

Areas covered: This review aimed to elaborate recent insights that supported the involvement of PTP-mediated pathways in the development of resistance to targeted therapy and immune-checkpoint therapy.

Expert opinion: This review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long-term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced-stage tumors.

Keywords

cancer treatment / combination therapy / drug resistance / protein tyrosine phosphatase

References

[1] Tonks NK. Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol. 2006;7(11):833-846.

[2] Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547(7664):413-418.

[3] Lopez JS, Banerji U. Combine and conquer: challenges for targeted therapy combinations in early phase trials. Nat Rev Clin Oncol. 2017;14(1):57-66.

[4] Mustelin T, Vang T, Bottini N. Protein tyrosine phosphatases and the immune response. Nat Rev Immunol. 2005;5(1):43-57.

[5] Vainonen JP, Momeny M, Westermarck J. Druggable cancer phosphatases. Sci Transl Med. 2021;13(588):eabe2967.

[6] Ostman A, Hellberg C, Bohmer FD. Protein-tyrosine phosphatases and cancer. Nat Rev Cancer. 2006;6(4):307-320.

[7] Wang PF, Cai HQ, Zhang CB, Li YM, Liu X, Wan JH, et al. Molecular and clinical characterization of PTPN2 expression from RNA-seq data of 996 brain gliomas. J Neuroinflammation. 2018;15(1):145.

[8] Dong L, Han D, Meng X, Xu M, Zheng C, Xia Q. Activating mutation of SHP2 establishes a tumorigenic phonotype through cell-autonomous and non-cell-autonomous mechanisms. Front Cell Dev Biol. 2021;9:630712.

[9] Bollu LR, Mazumdar A, Savage MI, Brown PH. Molecular Pathways: Targeting protein tyrosine phosphatases in cancer. Clin Cancer Res. 2017;23(9):2136-2142.

[10] Zhang J, Zhang F, Niu R. Functions of Shp2 in cancer. J Cell Mol Med. 2015;19(9):2075-2083.

[11] Xue JY, Zhao Y, Aronowitz J, Mai TT, Vides A, Qeriqi B, et al. Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition. Nature. 2020;577(7790):421-425.

[12] Dance M, Montagner A, Salles JP, Yart A, Raynal P. The molecular functions of Shp2 in the Ras/Mitogen-activated protein kinase (ERK1/2) pathway. Cell Signal. 2008;20(3):453-459.

[13] Easton JB, Royer AR, Middlemas DS. The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor. J Neurochem. 2006;97(3):834-845.

[14] Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19(8):533-552.

[15] Bologna-Molina R, Ogawa I, Mosqueda-Taylor A, Takata T, Sánchez-Romero C, Villarroel-Dorrego M, et al. Detection of MAPK/ERK pathway proteins and KRAS mutations in adenomatoid odontogenic tumors. Oral Dis. 2019;25(2):481-487.

[16] Ruess DA, Heynen GJ, Ciecielski KJ, Ai J, Berninger A, Kabacaoglu D, et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med. 2018;24(7):954-960.

[17] Nichols RJ, Haderk F, Stahlhut C, Schulze CJ, Hemmati G, Wildes D, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018;20(9):1064-1073.

[18] Fedele C, Ran H, Diskin B, Wei W, Jen J, Geer MJ, et al. SHP2 inhibition prevents adaptive resistance to MEK inhibitors in multiple cancer models. Cancer Discov. 2018;8(10):1237-1249.

[19] Yang H, Zhou X, Fu D, Le C, Wang J, Zhou Q, et al. Targeting RAS mutants in malignancies: successes, failures, and reasons for hope. Cancer Commun (Lond). 2023;43(1):42-74.

[20] Zhao Y, Murciano-Goroff YR, Xue JY, Ang A, Lucas J, Mai TT, et al. Diverse alterations associated with resistance to KRAS(G12C) inhibition. Nature. 2021;599(7886):679-683.

[21] Hong DS, Fakih MG, Strickler JH, Desai J, Durm GA, Shapiro GI, et al. KRAS(G12C) Inhibition with Sotorasib in Advanced Solid Tumors. N Engl J Med. 2020;383(13):1207-1217.

[22] Wang J, Zhao J, Zhong J, Li X, Fang J, Yu Y, et al. 653O Glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors. Ann Oncol. 2023;34:S459.

[23] Negrao MV, Cassier PA, Solomon B, Schuler M, Rohrberg K, Cresta S, et al. MA06.03 KontRASt-01: Preliminary safety and efficacy of JDQ443 + TNO155 in patients with advanced, KRAS G12C-mutated solid tumors. J Thorac Oncol. 2023;18(11, Supplement):S117-S118.

[24] Setton J, Zinda M, Riaz N, Durocher D, Zimmermann M, Koehler M, et al. Synthetic lethality in cancer therapeutics: the next generation. Cancer Discov. 2021;11(7):1626-1635.

[25] Wright S, Dobzhansky T. Genetics of natural populations; experimental reproduction of some of the changes caused by natural selection in certain populations of Drosophila pseudoobscura. Genetics. 1946;31(2):125-156.

[26] Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):162-174.

[27] Huang A, Garraway LA, Ashworth A, Weber B. Synthetic lethality as an engine for cancer drug target discovery. Nat Rev Drug Discov. 2020;19(1):23-38.

[28] Yar MS, Haider K, Gohel V, Siddiqui NA, Kamal A. Synthetic lethality on drug discovery: an update on cancer therapy. Expert Opin Drug Discov. 2020;15(7):823-832.

[29] Yin R, Eger G, Sarri N, Rorsman C, Heldin CH, Lennartsson J. Dual specificity phosphatase (DUSP)-4 is induced by platelet-derived growth factor -BB in an Erk1/2-, STAT3- and p53-dependent manner. Biochem Biophys Res Commun. 2019;519(3):469-474.

[30] Duan S, Moro L, Qu R, Simoneschi D, Cho H, Jiang S, et al. Loss of FBXO31-mediated degradation of DUSP6 dysregulates ERK and PI3K-AKT signaling and promotes prostate tumorigenesis. Cell Rep. 2021;37(3):109870.

[31] Ito T, Young MJ, Li R, Jain S, Wernitznig A, Krill-Burger JM, et al. Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers. Nat Genet. 2021;53(12):1664-1672.

[32] Goetz EM, Ghandi M, Treacy DJ, Wagle N, Garraway LA. ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors. Cancer Res. 2014;74(23):7079-7089.

[33] Leung GP, Feng T, Sigoillot FD, Geyer FC, Shirley MD, Ruddy DA, et al. Hyperactivation of MAPK signaling is deleterious to RAS/RAF-mutant melanoma. Mol Cancer Res. 2019;17(1):199-211.

[34] Chen YN, LaMarche MJ, Chan HM, Fekkes P, Garcia-Fortanet J, Acker MG, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016;535(7610):148-152.

[35] DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol. 2019;19(6):369-382.

[36] Henriksen A, Dyhl-Polk A, Chen I, Nielsen D. Checkpoint inhibitors in pancreatic cancer. Cancer Treat Rev. 2019;78:17-30.

[37] Abdou Y, Pandey M, Sarma M, Shah S, Baron J, Ernstoff MS. Mechanism-based treatment of cancer with immune checkpoint inhibitor therapies. Br J Clin Pharmacol. 2020;86(9):1690-1702.

[38] Shergold AL, Millar R, Nibbs RJB. Understanding and overcoming the resistance of cancer to PD-1/PD-L1 blockade. Pharmacol Res. 2019;145:104258.

[39] Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20(1):25-39.

[40] Neubert NJ, Schmittnaegel M, Bordry N, Nassiri S, Wald N, Martignier C, et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci Transl Med. 2018;10(436):eaan3311.

[41] Ramesh A, Kumar S, Nandi D, Kulkarni A. CSF1R- and SHP2-inhibitor-loaded nanoparticles enhance cytotoxic activity and phagocytosis in tumor-associated macrophages. Adv Mater. 2019;31(51):e1904364.

[42] Xu X, Hou B, Fulzele A, Masubuchi T, Zhao Y, Wu Z, et al. PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2. J Cell Biol. 2020;219(6):e201905085.

[43] Liu C, Lu H, Wang H, Loo A, Zhang X, Yang G, et al. Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin Cancer Res. 2021;27(1):342-354.

[44] Quintana E, Schulze CJ, Myers DR, Choy TJ, Mordec K, Wildes D, et al. Allosteric inhibition of SHP2 stimulates antitumor immunity by transforming the immunosuppressive environment. Cancer Res. 2020;80(13):2889-2902.

[45] Novartis Pharmaceuticals (Switzerland). (2019, July 30-2024, January 15). Phase Ib study of TNO155 in combination with spartalizumab or ribociclib in selected malignancies. Identifier NCT04000529. https://clinicaltrials.gov/study/NCT04000529?term=NCT04000529&rank=1

[46] Yuan X, Bu H, Zhou J, Yang CY, Zhang H. Recent advances of SHP2 inhibitors in cancer therapy: current development and clinical application. J Med Chem. 2020;63(20):11368-11396.

[47] Ajina A, Maher J. Strategies to address chimeric antigen receptor tonic signaling. Mol Cancer Ther. 2018;17(9):1795-1815.

[48] Chen J, Qiu S, Li W, Wang K, Zhang Y, Yang H, et al. Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness. Cell Res. 2023;33(5):341-354.

[49] Fernandes RA, Su L, Nishiga Y, Ren J, Bhuiyan AM, Cheng N, et al. Immune receptor inhibition through enforced phosphatase recruitment. Nature. 2020;586(7831):779-784.

[50] Bardhan K, Aksoylar HI, Le Bourgeois T, Strauss L, Weaver JD, Delcuze B, et al. Phosphorylation of PD-1-Y248 is a marker of PD-1-mediated inhibitory function in human T cells. Sci Rep. 2019;9(1):17252.

[51] Al Barashdi MA, Ali A, McMullin MF, Mills K. Protein tyrosine phosphatase receptor type C (PTPRC or CD45). J Clin Pathol. 2021;74(9):548-552.

[52] Li SKH, Martin A. Mismatch repair and colon cancer: mechanisms and therapies explored. Trends Mol Med. 2016;22(4):274-289.

[53] Shah SN, Hile SE, Eckert KA. Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes. Cancer Res. 2010;70(2):431-435.

[54] Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.

[55] Zhou F. Molecular mechanisms of IFN-gamma to up-regulate MHC class I antigen processing and presentation. Int Rev Immunol. 2009;28(3-4):239-260.

[56] Hoekstra ME, Bornes L, Dijkgraaf FE, Philips D, Pardieck IN, Toebes M, et al. Long-distance modulation of bystander tumor cells by CD8(+) T cell-secreted IFNγ. Nat Cancer. 2020;1(3):291-301.

[57] Grasso CS, Tsoi J, Onyshchenko M, Abril-Rodriguez G, Ross-Macdonald P, Wind-Rotolo M, et al. Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma. Cancer Cell. 2020;38(4):500-515.

[58] Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930-2940.

[59] Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S, Piot C, et al. Successful Anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity. 2018;49(6):1148-1161.

[60] Barrat FJ, Crow MK, Ivashkiv LB. Interferon target-gene expression and epigenomic signatures in health and disease. Nat Immunol. 2019;20(12):1574-1583.

[61] Liu S, Imani S, Deng Y, Pathak JL, Wen Q, Chen Y, et al. Targeting IFN/STAT1 pathway as a promising strategy to overcome radioresistance. Onco Targets Ther. 2020;13:6037-6050.

[62] LaFleur MW, Nguyen TH, Coxe MA, Miller BC, Yates KB, Gillis JE, et al. PTPN2 regulates the generation of exhausted CD8(+) T cell subpopulations and restrains tumor immunity. Nat Immunol. 2019;20(10):1335-1347.

[63] Katkeviciute E, Hering L, Montalban-Arques A, Busenhart P, Schwarzfischer M, Manzini R, et al. Protein tyrosine phosphatase nonreceptor type 2 controls colorectal cancer development. J Clin Invest. 2021;131(1):e140281.

[64] Baumgartner CK, Ebrahimi-Nik H, Iracheta-Vellve A, Hamel KM, Olander KE, Davis TGR, et al. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature. 2023;622(7984):850-862.

[65] Leonetti A, Sharma S, Minari R, Perego P, Giovannetti E, Tiseo M. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer. 2019;121(9):725-737.

[66] Novartis Pharmaceuticals (Switzerland). (2017, May 26-2025, May 16). Dose finding study of TNO155 in adult patients with advanced solid tumors. Identifier NCT03114319. https://clinicaltrials.gov/study/NCT03114319?term=NCT03114319&rank=1

[67] Revolution Medicines, Inc. (U.S.). (2019, July 2-2022, February 8). Dose-esc/exp RMC4630 & Cobi in relapsed/refractory solid tumors & RMC4630& Osi in EGFR+ locally adv/meta NSCLC. Identifier CT03989115. https://clinicaltrials.gov/study/NCT03989115?term=NCT03989115&rank=1

[68] Les B. (2020, December 15-2024, May 1). A dose escalation/expansion study of ERAS-601 in patients with advanced or metastatic solid tumors (FLAGSHP-1). Identifier CT04670679. https://clinicaltrials.gov/study/NCT04670679?term=NCT04670679&rank=1

[69] Samatar AA, Poulikakos PI. Targeting RAS-ERK signalling in cancer: promises and challenges. Nat Rev Drug Discov. 2014;13(12):928-942.

[70] Gebregiworgis T, Kano Y, St-Germain J, Radulovich N, Udaskin ML, Mentes A, et al. The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors. Nat Commun. 2021;12(1):6274.

[71] Lu H, Liu C, Velazquez R, Wang H, Dunkl LM, Kazic-Legueux M, et al. SHP2 inhibition overcomes RTK-mediated pathway reactivation in KRAS-mutant tumors treated with MEK inhibitors. Mol Cancer Ther. 2019;18(7):1323-1334.

[72] Mirati Therapeutics Inc. (U.S.). (2020, April 22-2024, March 1). Adagrasib in combination with TNO155 in patients with cancer (KRYSTAL 2). Identifier NCT04330664. https://clinicaltrials.gov/study/NCT04330664?term=NCT04330664&rank=1

[73] Novartis Pharmaceuticals (Switzerland). (2021, February 24-2027, January 8). Study of JDQ443 in patients with advanced solid tumors harboring the KRAS G12C mutation (KontRASt-01). Identifier NCT04699188. https://clinicaltrials.gov/study/NCT04699188?term=NCT04699188&rank=1

[74] Amgen (U.S). (2019, December 17-2027, December 31). Sotorasib activity in subjects with advanced solid tumors with KRAS p.G12C mutation (CodeBreak 101). Identifier NCT04185883. https://clinicaltrials.gov/study/NCT04185883?term=NCT04185883&rank=1

[75] Suzuki S, Yonesaka K, Teramura T, Takehara T, Kato R, Sakai H, et al. KRAS inhibitor resistance in MET-amplified KRAS (G12C) non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanisms. Clin Cancer Res. 2021;27(20):5697-5707.

[76] Wang J, Yao Z, Jonsson P, Allen AN, Qin ACR, Uddin S, et al. A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF(V600E)-mutant brain tumor. Cancer Discov. 2018;8(9):1130-1141.

[77] Zhang P, Kawakami H, Liu W, Zeng X, Strebhardt K, Tao K, et al. Targeting CDK1 and MEK/ERK overcomes apoptotic resistance in BRAF-mutant human colorectal cancer. Mol Cancer Res. 2018;16(3):378-389.

[78] Emile V. (2022, March 31-2024, July 1). Combination therapy of RMC-4630 and LY3214996 in metastatic KRAS mutant cancers (SHERPA). Identifier NCT04916236. https://clinicaltrials.gov/study/NCT04916236?term=NCT04916236&rank=1

[79] Wang J, Zhao J, Zhong J, Li X, Fang J, Yu Y, et al. 653O Glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors. Ann Oncol. 2023;34:S459.

[80] Skoulidis F, Li BT, Dy GK, Price TJ, Falchook GS, Wolf J, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381.

[81] Negrao MV, Cassier PA, Solomon B, Schuler M, Rohrberg K, Cresta S, et al. MA06.03 KontRASt-01: Preliminary safety and efficacy of JDQ443 + TNO155 in patients with advanced, KRAS G12C-mutated solid tumors. J Thorac Oncol. 2023;18(11, Supplement):S117-S118.

[82] Kanhailal AC, Mulero Sanchez A, Knikman JE, Bosma A, Bernards R, Huitema ADR, et al. 1630P Phase I/Ib study of SHP2-ERK inhibition in KRASm pancreatic cancer (SHERPA trial) and preclinical identification of potential resistance markers. Annals of Oncology. 2023;34:S902-S903.

[83] Stanford SM, Bottini N. Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders. Nat Rev Drug Discov. 2023;22(4):273-294.

[84] Liotti F, Kumar N, Prevete N, Marotta M, Sorriento D, Ieranò C, et al. PD-1 blockade delays tumor growth by inhibiting an intrinsic SHP2/Ras/MAPK signalling in thyroid cancer cells. J Exp Clin Cancer Res. 2021;40(1):22.

[85] Novartis Pharmaceuticals (Switzerland). (2019, July 30-2024, January 15). Phase Ib study of TNO155 in combination with spartalizumab or ribociclib in selected malignancies. Identifier NCT04000529. https://clinicaltrials.gov/study/NCT04000529?term=NCT04000529&rank=1

[86] Yu M, Peng Z, Qin M, Liu Y, Wang J, Zhang C, et al. Interferon-γ induces tumor resistance to anti-PD-1 immunotherapy by promoting YAP phase separation. Mol Cell. 2021;81(6):1216-1230.e9.

[87] Calico Life Sciences LLC (U.S.). (2020, June 3-2026, April 30). First in human study with ABBV-CLS-579 when given alone and in combination in participants with locally advanced or metastatic tumors. Identifier NCT04417465. https://clinicaltrials.gov/study/NCT04417465?term=NCT04417465&rank=1

[88] Calico Life Sciences LLC (U.S.). (2021, March 9-2026, October 5). A Phase 1 study with ABBV-CLS-484 in subjects with locally advanced or metastatic tumors. Identifier NCT04777994. https://clinicaltrials.gov/study/NCT04777994?term=NCT04777994&rank=1

[89] Du L, Ji Y, Xin B, Zhang J, Lu LC, Glass CK, et al. Shp2 deficiency in Kupffer cells and hepatocytes aggravates hepatocarcinogenesis by recruiting non-Kupffer macrophages. Cell Mol Gastroenterol Hepatol. 2023;15(6):1351-1369.

[90] Bard-Chapeau EA, Li S, Ding J, Zhang SS, Zhu HH, Princen F, et al. Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell. 2011;19(5):629-639.

[91] Kim M, Morales LD, Lee CJ, Olivarez SA, Kim WJ, Hernandez J, et al. Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation. Oncogene. 2020;39(21):4241-4256.

[92] Liu M, Gao S, Elhassan RM, Hou X, Fang H. Strategies to overcome drug resistance using SHP2 inhibitors. Acta Pharm Sin B. 2021;11(12):3908-3924.

[93] Stanford SM, Bottini N. Targeting tyrosine phosphatases: time to end the stigma. Trends Pharmacol Sci. 2017;38(6):524-540.

[94] Song Z, Wang M, Ge Y, Chen XP, Xu Z, Sun Y, et al. Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies. Acta Pharm Sin B. 2021;11(1):13-29.

[95] Fan Z, Tian Y, Chen Z, Liu L, Zhou Q, He J, et al. Blocking interaction between SHP2 and PD-1 denotes a novel opportunity for developing PD-1 inhibitors. EMBO Mol Med. 2020;12(6):e11571.

[96] McDonald ER,, de Weck A, Schlabach MR, Billy E, Mavrakis KJ, Hoffman GR, et al. Project DRIVE: A Compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell. 2017;170(3):577.

[97] Haley B, Roudnicky F. Functional genomics for cancer drug target discovery. Cancer Cell. 2020;38(1):31-43.

[98] Weber J, Braun CJ, Saur D, Rad R. In vivo functional screening for systems-level integrative cancer genomics. Nat Rev Cancer. 2020;20(10):573-593.

[99] Cheng F, Kovács IA, Barabási AL. Network-based prediction of drug combinations. Nat Commun. 2019;10(1):1197.

[100] Ryall KA, Tan AC. Systems biology approaches for advancing the discovery of effective drug combinations. J Cheminform. 2015;7:7.

[101] Liao JJZ, Zhou F, Zhou H, Petruzzelli L, Hou K, Asatiani E. A hybrid design for dose-finding oncology clinical trials. Int J Cancer. 2022;151(9):1602-1610.

[102] Li J, Zhao J, Cao B, Fang J, Li X, Wang M, et al. A phase I/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors. J Clin Oncol. 2022;40(16_suppl):3089.

RIGHTS & PERMISSIONS

2024 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.