Research Progress on the Mechanism of Acquired Resistance to Cisplatin and PARP Inhibitors in Epithelial Ovarian Cancer

doi:10.12280/gjfckx.20260302

Abstract

Abstract:

Epithelial ovarian cancer is the most common pathological type of ovarian cancer. The standard first-line treatment regimen consists of platinum-based chemotherapy combined with maintenance therapy using poly (ADP-ribose) polymerase (PARP) inhibitors. However, acquired resistance severely impacts long-term patient survival. Cisplatin resistance involves enhanced drug efflux and detoxification, increased DNA damage repair capacity [especially through homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathways], abnormal epigenetic regulation, tumor stem cell mediated resistance, tumor microenvironment mediated resistance, inhibition of cell death pathways, and tumor metabolic reprogramming. PARP inhibitors resistance include restoration of HRR function, restoration of replication fork stability, alterations in drug targets, non-HRR-dependent mechanisms [such as drug efflux pumps, epigenetic changes, nuclear factor-κB pathway abnormalities], and microRNA regulation. Both types of resistance are highly dependent on the integrity of DNA damage repair pathways and exhibit cross-resistance at specific nodes, such as BRCA1 secondary splice-site mutations (SSMs), lymphoid enhancer-binding factor 1 (LEF1), lactic acid-X-ray repair cross-complementing protein 4 (XRCC4) axis, and the helicase-like transcription factor (HELQ) - PARP1 interaction. Based on these mechanisms, strategies such as combining ataxia telangiectasia mutated and Rad3-related kinase (ATR) inhibitors with PARP inhibitors, targeting LEF1 or HELQ, and inducing ferroptosis hold promise for overcoming resistance.

Key words: Carcinoma, ovarian epithelial, Drug resistance, multiple, Cisplatin, Poly (ADP-ribose) polymerase inhibitors, Therapy

WAN Tao, TAO Yao, WANG Hou-mei, XIAO Zi-wen. Research Progress on the Mechanism of Acquired Resistance to Cisplatin and PARP Inhibitors in Epithelial Ovarian Cancer[J]. Journal of International Obstetrics and Gynecology, 2026, 53(5): 556-562.

References 47

[1]	Dogan H, Liptay M, Barbosa JS, et al. MDC1 counteracts replication fork reversal and mediates chemosensitivity in BRCA1/2-deficient tumors[J]. Oncogene, 2026, 45(4):491-504. doi: 10.1038/s41388-025-03659-8.
[2]	Li H, Sheng JJ, Zheng SA, et al. Platinum-resistant ovarian cancer: From mechanisms to treatment strategies[J]. Genes Dis, 2026, 13(2):101801. doi: 10.1016/j.gendis.2025.101801.
[3]	Zheng Z, Li X, Yang B, et al. SORL1 stabilizes ABCB1 to promote cisplatin resistance in ovarian cancer[J]. Funct Integr Genomics, 2023, 23(2):147. doi: 10.1007/s10142-023-01075-3.
[4]	Guo J, Sun Y, Liu G. The mechanism of copper transporters in ovarian cancer cells and the prospect of cuproptosis[J]. J Inorg Biochem, 2023, 247:112324. doi: 10.1016/j.jinorgbio.2023.112324.
[5]	Lukanović D, Herzog M, Kobal B, et al. The contribution of copper efflux transporters ATP7A and ATP7B to chemoresistance and personalized medicine in ovarian cancer[J]. Biomed Pharmacother, 2020, 129:110401. doi: 10.1016/j.biopha.2020.110401. pmid: 32570116
[6]	Zhang Y, Qiu JG, Wang W, et al. Suppression of CYLD by HER3 confers ovarian cancer platinum resistance via inhibiting apoptosis and by inducing drug efflux[J]. Exp Hematol Oncol, 2025, 14(1):21. doi: 10.1186/s40164-025-00620-z. pmid: 40012003
[7]	Wang L, Wang X, Zhu X, et al. Drug resistance in ovarian cancer: from mechanism to clinical trial[J]. Mol Cancer, 2024, 23(1):66. doi: 10.1186/s12943-024-01967-3. pmid: 38539161
[8]	Nesic K, Krais JJ, Wang Y, et al. BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance[J]. Mol Cancer, 2024, 23(1):158. doi: 10.1186/s12943-024-02048-1. pmid: 39103848
[9]	Miras I, Vázquez-Gutierrez I, Estévez-García P, et al. DNA repair pathways in ovarian cancer: Implications for therapy and resistance[J]. Biomed Pharmacother, 2025, 193:118719. doi: 10.1016/j.biopha.2025.118719.
[10]	Lu J, Zhu J, Zhang H, et al. Lactate Enhances Non-Homologous End Joining Repair and Chemoresistance Through Facilitating XRCC4-LIG4 Complex Assembly in Ovarian Cancer[J]. Biomedicines, 2025, 13(12):2949. doi: 10.3390/biomedicines13122949.
[11]	Dey G, Bharti R, Braley C, et al. LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer[J]. J Ovarian Res, 2023, 16(1):122. doi: 10.1186/s13048-023-01194-2. pmid: 37370140
[12]	Nakatsuka E, Tan L, Cunneen B, et al. Characterization of DNA damage repair pathway utilization in high-grade serous ovarian cancers yields rational therapeutic approaches[J]. Transl Oncol, 2024, 50:102119. doi: 10.1016/j.tranon.2024.102119.
[13]	Song K, Artibani M. The role of DNA methylation in ovarian cancer chemoresistance: A narrative review[J]. Health Sci Rep, 2023, 6(5):e1235. doi: 10.1002/hsr2.1235. pmid: 37123549
[14]	Pan X, Shi X, Zhang H, et al. Exosomal miR-4516 derived from ovarian cancer stem cells enhanced cisplatin tolerance in ovarian cancer by inhibiting GAS7[J]. Gene, 2024, 927:148738. doi: 10.1016/j.gene.2024.148738.
[15]	Wang W, Zhou Y, Wang J, et al. Targeting Ovarian Cancer Stem Cells by Dual Inhibition of the Long Noncoding RNA HOTAIR and Lysine Methyltransferase EZH2[J]. Mol Cancer Ther, 2024, 23(11):1666-1679. doi: 10.1158/1535-7163.MCT-23-0314. pmid: 39039946
[16]	Chen M, Huang L, Zhao S, et al. Ivosidenib enhances cisplatin sensitivity in ovarian cancer by reducing cancer cell stemness[J]. Cancer Drug Resist, 2025, 8:20. doi: 10.20517/cdr.2025.51.
[17]	Deng Z, Li B, Wang W, et al. TCEB2/HIF1A signaling axis promotes chemoresistance in ovarian cancer cells by enhancing glycolysis and angiogenesis[J]. Eur J Med Res, 2024, 29(1):456. doi: 10.1186/s40001-024-02050-9. pmid: 39261917
[18]	Chatterjee B, Sarkar M, Ghosh D, et al. Tumor-associated macrophages contribute to cisplatin resistance via regulating Pol η-mediated translesion DNA synthesis in ovarian cancer[J]. Cell Mol Life Sci, 2025, 82(1):220. doi: 10.1007/s00018-025-05731-8. pmid: 40437303
[19]	Karkempetzaki AI, Schatton T, Barthel SR. Galectin-9-An Emerging Glyco-Immune Checkpoint Target for Cancer Therapy[J]. Int J Mol Sci, 2025, 26(16):7998. doi: 10.3390/ijms26167998.
[20]	Farsinejad S, Centeno D, Savas-Carstens J, et al. Suppression of Ovarian Cancer Cell Proliferation Is Associated with Upregulation of Cell-Matrix Adhesion Programs and Integrin-β4-Induced Cell Protection from Cisplatin[J]. Cancers(Basel), 2025, 17(9):1472 doi: 10.3390/cancers17091472.
[21]	Wang H, Zhang P, Cheng Q, et al. Heme oxygenase-1 (HO-1) depletion promotes ferroptosis to reverse cisplatin-resistance via enhancing NCOA4-mediated ferritinophagy in ovarian cancer[J]. Int J Biol Macromol, 2025, 327(Pt 2):147257. doi: 10.1016/j.ijbiomac.2025.147257.
[22]	Liu X, Wang J, Liu Y, et al. Knockdown of TOP2A reverses cisplatin resistance in ovarian cancer by inhibiting EMT via ferroptosis mediated by the TP53/GPX4/SLC7A11 axis[J]. Front Immunol, 2025, 16:1675373. doi: 10.3389/fimmu.2025.1675373.
[23]	Yang YF, Rui L, Zhang BW, et al. Autophagy regulation in ovarian cancer chemoresistance: Molecular mechanisms and emerging frontiers[J]. Life Sci, 2025, 380:123966. doi: 10.1016/j.lfs.2025.123966.
[24]	Wu J, Chen H, Wang S, et al. miR-512-3p/RPS6KA2 Axis Regulates Cisplatin Resistance in Ovarian Cancer via Autophagy and Ferroptosis[J]. Oncol Res, 2025, 34(1):26. doi: 10.32604/or.2025.070542.
[25]	Cardenas H, Wang Y, Zhao G, et al. Metabolic Dependency on De Novo Pyrimidine Synthesis Is a Targetable Vulnerability in Platinum-Resistant Ovarian Cancer[J]. Cancer Res, 2026, 86(2):387-401. doi: 10.1158/0008-5472.CAN-25-0043.
[26]	Wu Y, Zeng Y, Wu Y, et al. HIF-1α-induced long noncoding RNA LINC02776 promotes drug resistance of ovarian cancer by increasing polyADP-ribosylation[J]. Clin Transl Med, 2025, 15(3):e70244. doi: 10.1002/ctm2.70244.
[27]	Kulkarni S, Seneviratne N, Tosun Ç, et al. PARP inhibitors in ovarian cancer: Mechanisms of resistance and implications to therapy[J]. DNA Repair(Amst), 2025, 149:103830. doi: 10.1016/j.dnarep.2025.103830.
[28]	Irving E, Morcavallo A, Vohhodina-Tretjakova J, et al. An Inducible BRCA1 Expression System with In Vivo Applicability Uncovers Activity of the Combination of ATR and PARP Inhibitors to Overcome Therapy Resistance[J]. Cancers(Basel), 2026, 18(2):309. doi: 10.3390/cancers18020309.
[29]	Sun Y, Patterson-Fortin J, Han S, et al. 53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer[J]. Nat Commun, 2024, 15(1):6676. doi: 10.1038/s41467-024-50999-2. pmid: 39107288
[30]	Paes Dias M, Tripathi V, van der Heijden I, et al. Loss of nuclear DNA ligase Ⅲ reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps[J]. Mol Cell, 2021, 81(22):4692-4708.e9. doi: 10.1016/j.molcel.2021.09.005.
[31]	Han F, Qi G, Li R, et al. USP28 promotes PARP inhibitor resistance by enhancing SOX9-mediated DNA damage repair in ovarian cancer[J]. Cell Death Dis, 2025, 16(1):305. doi: 10.1038/s41419-025-07647-4.
[32]	Duval AJ, Seker-Polat F, Rogozinska M, et al. SOX9 drives a stem-like transcriptional state and platinum resistance in high-grade serous ovarian cancer[J]. J Clin Invest, 2025, 135(19):e186467. doi: 10.1172/JCI186467.
[33]	Tang M, Li S, Zhu Z, et al. USP37 counteracts HLTF to protect damaged replication forks and promote survival of BRCA1-deficient cells and PARP inhibitor resistance[J]. Nucleic Acids Res, 2025, 53(12):gkaf544. doi: 10.1093/nar/gkaf544.
[34]	Wu W, Wu W, Xie X, et al. DNMT1 is required for efficient DSB repair and maintenance of replication fork stability, and its loss reverses resistance to PARP inhibitors in cancer cells[J]. Oncogene, 2025, 44(27):2283-2302. doi: 10.1038/s41388-025-03409-w. pmid: 40234721
[35]	Qi G, Ma H, Chen J, et al. TTK activates ATR through RPA2 phosphorylation to promote olaparib resistance in ovarian cancer[J]. Commun Biol, 2025, 8(1):1011. doi: 10.1038/s42003-025-08444-7.
[36]	Habiburrahman M, Flanagan JM. Epigenetic mechanisms of PARP inhibitor resistance in ovarian cancer: A systematic review with bioinformatic analysis of clinically actionable genes[J]. Crit Rev Oncol Hematol, 2026, 217:105012. doi: 10.1016/j.critrevonc.2025.105012.
[37]	Liu C, Li J, Xu F, et al. PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer[J]. Mol Cancer, 2024, 23(1):111. doi: 10.1186/s12943-024-02025-8. pmid: 38778348
[38]	Huang L, Zhu M, Chen M, et al. LEF1 confers resistance to DNA-damaging chemotherapies through upregulation of PARP1 and NUMA1 in ovarian cancer[J]. Oncogene, 2025, 44(43):4130-4144. doi: 10.1038/s41388-025-03561-3.
[39]	Tan S, Zhu F, Li Y, et al. HELQ upregulates PARP1 to drive platinum resistance and predict therapeutic response in ovarian cancer[J]. Transl Oncol, 2025, 57:102416. doi: 10.1016/j.tranon.2025.102416.
[40]	Ravindranathan R, Somuncu O, da Costa A, et al. PARG inhibitor sensitivity correlates with accumulation of single-stranded DNA gaps in preclinical models of ovarian cancer[J]. Proc Natl Acad Sci U S A, 2024, 121(47):e2413954121. doi: 10.1073/pnas.2413954121.
[41]	Miller RE, El-Shakankery KH, Lee JY. PARP inhibitors in ovarian cancer: overcoming resistance with combination strategies[J]. J Gynecol Oncol, 2022, 33(3):e44. doi: 10.3802/jgo.2022.33.e44. pmid: 35320891
[42]	Macdonald CJ, McWhirter A, Vaidyanathan A, et al. Identification of novel drug-specific PARP inhibitor resistance mechanisms in ovarian cancer-implications for clinical practice[J]. Br J Cancer, 2026, 135(2):290-302. doi: 10.1038/s41416-026-03423-z.
[43]	Onji H, Tate S, Sakaue T, et al. Schlafen 11 further sensitizes BRCA-deficient cells to PARP inhibitors through single-strand DNA gap accumulation behind replication forks[J]. Oncogene, 2024, 43(32):2475-2489. doi: 10.1038/s41388-024-03094-1. pmid: 38961202
[44]	Song C, Lin Y, Cai C, et al. LOXL2 reduces susceptibility to PARP inhibitors by promoting super-enhancer-regulated DNA damage repair in high-grade serous ovarian cancer[J]. Oncogene, 2025, 44(32):2864-2875. doi: 10.1038/s41388-025-03466-1.
[45]	Guo H, Lu R, Yuan S, et al. Activation of cGAS confers PARP inhibitor resistance in ovarian cancer via the TBK1-IRF3 axis[J]. Int J Clin Exp Pathol, 2024, 17(11):429-438. doi: 10.62347/XOPN6908.
[46]	Teng K, Ma H, Gai P, et al. SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway[J]. Cell Death Discov, 2025, 11(1):29. doi: 10.1038/s41420-025-02309-y. pmid: 39875359
[47]	Choi YE, Meghani K, Brault ME, et al. Platinum and PARP Inhibitor Resistance Due to Overexpression of MicroRNA-622 in BRCA1-Mutant Ovarian Cancer[J]. Cell Rep, 2016, 14(3):429-439. doi: 10.1016/j.celrep.2015.12.046. pmid: 26774475