Ovarian cancer resistance to PARPi and platinum-containing chemotherapy

Abstract

Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies. Although initial response to therapy is observed, recurrence and ultimately chemoresistance result in overall therapeutic failure. This pattern has been evident with platinum therapy since the 1980s. Significant excitement surrounded the approval of poly (ADP-ribose) polymerase inhibition (PARPi) as a novel therapeutic option, especially with the advent of personalized medicine, but resistance has similarly developed to these treatments. Novel agents are constantly being sought, but if the obstacle of chemoresistance remains, the durability of responses will remain tenuous. Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured. Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes.

Keywords

Epithelial ovarian cancer / chemoresistance / platinum resistance / poly (ADP-ribose) polymerase inhibitor resistance / tumor microenvironment

References

[1] Damia G.Platinum resistance in ovarian cancer: role of DNA repair.Cancers (Basel)2019;11:119 PMCID:PMC6357127

[2] McFadden M,Oprea-Ilies G.Nano-based drug delivery and targeting to overcome drug resistance of ovarian cancers.Cancers (Basel)2021;13:5480 PMCID:PMC8582784

[3] Freimund AE,Christie EL.Mechanisms of drug resistance in high-grade serous ovarian cancer.Hematol Oncol Clin North Am2018;32:983-96

[4] Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma.Nature2011;474:609-15

[5] Rose M,O'Byrne K,Bolderson E.PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance.Front Cell Dev Biol2020;8:564601 PMCID:PMC7509090

[6] McMullen M,Madariaga A.Overcoming platinum and PARP-inhibitor resistance in ovarian cancer.Cancers (Basel)2020;12:1607 PMCID:PMC7352566

[7] Klotz DM.Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies?.Arch Gynecol Obstet2020;302:1087-102 PMCID:PMC7524817

[8] Chiappa M,Bertoni F,Damia G.Overcoming PARPi resistance: preclinical and clinical evidence in ovarian cancer.Drug Resist Updat2021;55:100744

[9] Jiang X,Li W,Zhang Z.PARP inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms.J Cell Mol Med2019;23:2303-13 PMCID:PMC6433712

[10] Hedditch EL,Russell AJ.Australian Ovarian Cancer Study GroupABCA transporter gene expression and poor outcome in epithelial ovarian cancer.J Natl Cancer Inst2014;106:dju149 PMCID:PMC4110473

[11] Jackson SP.The DNA-damage response in human biology and disease.Nature2009;461:1071-8 PMCID:PMC2906700

[12] Blackford AN.ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response.Mol Cell2017;66:801-17

[13] Friedberg EC.A brief history of the DNA repair field.Cell Res2008;18:3-7

[14] Galluzzi L,Vitale I.Molecular mechanisms of cisplatin resistance.Oncogene2012;31:1869-83

[15] Costa RM,Galhardo Rda S,Menck CF.The eukaryotic nucleotide excision repair pathway.Biochimie2003;85:1083-99

[16] Stergiou L,Doukoumetzidis K.NER and HR pathways act sequentially to promote UV-C-induced germ cell apoptosis in caenorhabditis elegans.Cell Death Differ2011;18:897-906 PMCID:PMC3131928

[17] Martin LP,Schilder RJ.Platinum resistance: the role of DNA repair pathways.Clin Cancer Res2008;14:1291-5

[18] Duan M,Liu KJ.Role of nucleotide excision repair in cisplatin resistance.Int J Mol Sci2020;21:9248 PMCID:PMC7730652

[19] Ferry KV,Johnson SW.Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF.Biochem Pharmacol2000;60:1305-13

[20] Selvakumaran M,Bao R,Hamilton TC.Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines.Cancer Res2003;63:1311-6

[21] Ha DH,Kim S.Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer.Sci Rep2020;10:9930 PMCID:PMC7303169

[22] Cummings M,Orsi NM.Targeting the tumour microenvironment in platinum-resistant ovarian cancer.Semin Cancer Biol2021;77:3-28

[23] Wang Y,Cruz C.kConFab InvestigatorsThe BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP INhibition and cisplatin.Cancer Res2016;76:2778-90 PMCID:PMC4874568

[24] Lin KK,Oza AM..BRCA9:210-9

[25] Bristow RG.Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability.Nat Rev Cancer2008;8:180-92

[26] Brown JM.Exploiting tumour hypoxia in cancer treatment.Nat Rev Cancer2004;4:437-47

[27] Chen J,Yuan Y.Exploiting the acquired vulnerability of cisplatin-resistant tumors with a hypoxia-amplifying DNA repair-inhibiting (HYDRI) nanomedicine.Sci Adv2021;7:eabc5267 PMCID:PMC7997498

[28] Sahoo SS,Hondermarck H.The emerging role of the microenvironment in endometrial cancer.Cancers (Basel)2018;10:408 PMCID:PMC6266917

[29] Patch AM,Etemadmoghadam D.Australian Ovarian Cancer Study GroupWhole-genome characterization of chemoresistant ovarian cancer.Nature2015;521:489-94

[30] Ojalvo LS,Wang TL.Tumor-associated macrophages and the tumor immune microenvironment of primary and recurrent epithelial ovarian cancer.Hum Pathol2018;74:135-47

[31] Martin de la Fuente L,Arildsen NS.PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma.Virchows Arch2020;477:83-91 PMCID:PMC7320055

[32] Sato E,Ahn J.Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer.Proc Natl Acad Sci U S A2005;102:18538-43 PMCID:PMC1311741

[33] Hwang WT,Tahirovic E,Coukos G.Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis.Gynecol Oncol2012;124:192-8 PMCID:PMC3298445

[34] Zhao G,Matei D.Ovarian cancer-why lipids matter.Cancers (Basel)2019;11:1870 PMCID:PMC6966536

[35] Etzerodt A,Doktor TK.Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer.J Exp Med2020;217:e20191869 PMCID:PMC7144521

[36] Ladanyi A,Kenny HA.Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis.Oncogene2018;37:2285-301 PMCID:PMC5920730

[37] Chen RR,Xuan Y.Targeting of lipid metabolism with a metabolic inhibitor cocktail eradicates peritoneal metastases in ovarian cancer cells.Commun Biol2019;2:281 PMCID:PMC6668395

[38] Pieterse Z,Singomat T.Ovarian cancer stem cells and their role in drug resistance.Int J Biochem Cell Biol2019;106:117-26

[39] Chen X,Zhang Z,Cheng W.Cancer stem cells, epithelial-mesenchymal transition, and drug resistance in high-grade ovarian serous carcinoma.Hum Pathol2013;44:2373-84 PMCID:PMC3797876

[40] Mensah LB,Li J.Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum-based drug resistance therapy in ovarian cancer.Bioeng Transl Med2019;4:e10131 PMCID:PMC6584097

[41] Etemadmoghadam D,Beroukhim R.AOCS Study GroupIntegrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas.Clin Cancer Res2009;15:1417-27 PMCID:PMC2670486

[42] Altaha R,Yu JJ.Excision repair cross complementing-group 1: gene expression and platinum resistance.Int J Mol Med2004;14:959-70

[43] Helleman J,Dinjens WN.Mismatch repair and treatment resistance in ovarian cancer.BMC Cancer2006;6:201 PMCID:PMC1557864

[44] Laufs V,Sbiera S.ERCC1 as predictive biomarker to platinum-based chemotherapy in adrenocortical carcinomas.Eur J Endocrinol2018;178:181-8

[45] Lee SM,Blackhall F.Randomized prospective biomarker trial of ERCC1 for comparing platinum and nonplatinum therapy in advanced non-small-cell lung cancer: ERCC1 trial (ET).J Clin Oncol2017;35:402-11

[46] Dabholkar M,Weber C,Egwuagu C.ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients.J Natl Cancer Inst1992;84:1512-7

[47] Kondrashova O,Shield-Artin K.AOCS Study GroupSecondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma.Cancer Discov2017;7:984-98 PMCID:PMC5612362

[48] Khan MA,Sudan SK.Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management.Semin Cancer Biol2021;77:99-109 PMCID:PMC8665066

[49] Lawlor D,Busschots S.PARP inhibitors as P-glyoprotein substrates.J Pharm Sci2014;103:1913-20

[50] Tothill RW,George J.Australian Ovarian Cancer Study GroupNovel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome.Clin Cancer Res2008;14:5198-208

[51] Lianidou E.Liquid biopsies.Genes Chromosomes Cancer2019;58:219-32

[52] Konecny GE,Hamidi H.Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer.J Natl Cancer Inst2014;106:dju249 PMCID:PMC4271115

[53] Macintyre G,De Silva D.Copy number signatures and mutational processes in ovarian carcinoma.Nat Genet2018;50:1262-70 PMCID:PMC6130818

[54] COSMIC 2021. Mutational Signatures. Available from: https://cancer.sanger.ac.uk/signatures/ [Last accessed on 20 Apr 2022]

[55] Alexandrov LB,Wedge DC.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature2013;500:415-21 PMCID:PMC3776390

[56] Matthews BG,Wong-Brown MW.Epigenetic mechanisms and therapeutic targets in chemoresistant high-grade serous ovarian cancer.Cancers (Basel)2021;13:5993 PMCID:PMC8657426

[57] U.S. National Library of Medicine. A study to examine olaparib maintenance retreatment in patients with epithelial ovarian cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT03106987 [Last accessed on 20 Apr 2022]

[58] Gajan A,Kim S,Wu GS.Analysis of adaptive olaparib resistance effects on cisplatin sensitivity in triple negative breast cancer cells.Front Oncol2021;11:694793 PMCID:PMC8339968

[59] Gray HJ,Fleming GF.Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies.Gynecol Oncol2018;148:507-14

[60] Zhang J,Tian Y.Effects of poly (ADP-ribosyl) polymerase (PARP) inhibitor on cisplatin resistance & proliferation of the ovarian cancer C13* cells.Indian J Med Res2013;137:527-32 PMCID:PMC3705661

[61] Lheureux S,Garg S.EVOLVE: a multicenter open-label single-arm clinical and translational phase II trial of cediranib plus olaparib for ovarian cancer after PARP inhibition progression.Clin Cancer Res2020;26:4206-15

[62] U.S. National Library of Medicine. Testing the combination of cediranib and olaparib in comparison to each drug alone or other chemotherapy in recurrent platinum-resistant ovarian cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT02502266. [Last accessed on 20 Apr 2022].

[63] Matulonis UA,Barry WT.Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer.Ann Oncol2017;28:512-8 PMCID:PMC5834157

[64] Konstantinopoulos PA,Birrer M.Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial.The Lancet Oncology2019;20:570-80 PMCID:PMC7025391

[65] Attard G,Olmos D.Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer.Cancer Res2009;69:2912-8