Molecular mechanisms of resistance to platinum based chemotherapy in serous ovarian cancer: the role of genetic polymorphism

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Epithelial ovarian cancer, primarily high-grade serous ovarian cancer, is a tumor characterized by a high probability of recurrence following primary treatment, which consists of cytoreductive surgery combined with platinum-based chemotherapy. Despite standardized therapeutic approaches, the platinum-free interval, progression-free survival, and overall survival vary substantially. Beyond somatic tumor characteristics and the completeness of cytoreduction, a significant portion of this variability may be driven by germline single-nucleotide polymorphisms (SNPs) in genes encoding proteins responsible for drug transport, detoxification, and DNA repair. The objective of this review is to systematize data on the molecular mechanisms of platinum sensitivity and resistance in serous ovarian cancer, with an emphasis on the role of germline structural DNA variants (SNPs), discuss the limitations of existing data, and outline directions for future research.

A literature search was performed in PubMed, Scopus and Google Scholar using the following keywords: “high-grade serous ovarian cancer”, “platinum”, “carboplatin”, “cisplatin”, “polymorphism”, “SNP”, “pharmacogenetics”, “progression-free survival”, and “platinum resistance”. Priority was given to studies with a sample size of ≥100 ovarian cancer patients and those with independent validation or a meta-analysis. A number of studies with smaller sample sizes were included due to the particular significance of their results and are specified in the text. The most reproducible associations with platinum resistance are demonstrated by SNPs in genes involved in nucleotide excision repair pathways (ERCC1, ERCC5), platinum transport and excretion (ABCB1), and specific signaling pathways (STAT3, FGFR4). Many candidate associations remain controversial owing to variations in the definition of platinum resistance, small sample sizes, heterogeneity in treatment regimens, and interethnic differences in allele frequencies and effects.

About the authors

Kristina V. Subbotina

Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: ksubbotina01@gmail.com
ORCID iD: 0000-0002-0515-5699
Russian Federation, 8 Akademika Lavrentieva St., Novosibirsk 630090

A. V. Tarkhov

Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences; City Clinical Hospital No. 1, Novosibirsk

Email: ksubbotina01@gmail.com
ORCID iD: 0000-0001-7805-1914
Russian Federation, 8 Akademika Lavrentieva St., Novosibirsk 630090; 6 Zalessky St., Novosibirsk 630047

U. A. Boyarskikh

Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences

Email: ksubbotina01@gmail.com
ORCID iD: 0000-0002-5660-2276
Russian Federation, 8 Akademika Lavrentieva St., Novosibirsk 630090

N. E. Kushlinskii

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: ksubbotina01@gmail.com
ORCID iD: 0000-0002-3898-4127
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522

M. L. Filipenko

Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences; Federal State Budgetary Institution, National Medical Research Center of Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Ministry of Health of Russia

Email: ksubbotina01@gmail.com
ORCID iD: 0000-0002-8950-5368

Institute of Reproductive Genetics 

Russian Federation, 8 Akademika Lavrentieva St., Novosibirsk 630090; 4 Akademika Oparina St., Moscow 117997

References

  1. Ovarian cancer/fallopian tube cancer/primary peritoneal cancer. Clinical guidelines, Ministry of Health of Russia. Moscow, 2024. (In Russ.).
  2. Steffensen K.D., Waldstrøm M., Jeppesen U. et al. Prediction of response to chemotherapy by ERCC1 immunohistochemistry and ERCC1 polymorphism in ovarian cancer. Int J Gynecol Cancer 2008;18(4):702–10. doi: 10.1111/j.1525-1438.2007.01068.x
  3. The state of oncological care for the Russian population in 2023. Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2024. 262 p. (In Russ.).
  4. Marmé F., Hielscher T., Hug S. et al. Fibroblast growth factor receptor 4 gene (FGFR4) 388Arg allele predicts prolonged survival and platinum sensitivity in advanced ovarian cancer. Int J Cancer 2012;131(4):E586–91. doi: 10.1002/ijc.27329
  5. Braun R., Finney R., Yan C. et al. Discovery analysis of TCGA data reveals association between germline genotype and survival in ovarian cancer patients. PLoS One 2013;8(3):e55037. doi: 10.1371/journal.pone.0055037
  6. Mitamura T., Zhai T., Hatanaka K.C. et al. Germline PRDM1 variant rs2185379 in long-term recurrence-free survivors of advanced ovarian cancer. Pharmgenomics Pers Med 2022;15:977–84. doi: 10.2147/PGPM.S387120
  7. Konopka B., Szafron L.M., Kwiatkowska E. et al. The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome. Oncotarget 2016;7(41):67412–24. doi: 10.18632/oncotarget.11822
  8. Moxley K.M., Benbrook D.M., Queimado L. et al. The role of single nucleotide polymorphisms of the ERCC1 and MMS19 genes in predicting platinum-sensitivity, progression-free and overall survival in advanced epithelial ovarian cancer. Gynecol Oncol 2013;130(2):377–82. doi: 10.1016/j.ygyno.2013.04.054
  9. Gagno S., Poletto E., Bartoletti M. et al. A TGF-β associated genetic score to define prognosis and platinum sensitivity in advanced epithelial ovarian cancer. Gynecol Oncol 2020;156(1):233–42. doi: 10.1016/j.ygyno.2019.10.019
  10. Li H., Dai H., Shi T. Potentially functional variants in nucleotide excision repair pathway genes predict platinum treatment response of Chinese ovarian cancer patients. Carcinogenesis 2020;41(9):1229–37. doi: 10.1093/carcin/bgaa075
  11. Li H., Chen L., Tong X. Functional genetic variants of CTNNBIP1 predict platinum treatment response of Chinese epithelial ovarian cancer patients. J Cancer 2020;11(23):6850–60. doi: 10.7150/jca.48218
  12. Khrunin A.V., Khokhrin D.V., Moisseev A.A. et al. Pharmacogenomic assessment of cisplatin-based chemotherapy outcomes in ovarian cancer. Pharmacogenomics 2014;15(3):329–37. doi: 10.2217/pgs.13.237
  13. Huang R.S., Johnatty S.E., Gamazon E.R. et al. Platinum sensitivity-related germline polymorphism discovered via a cell-based approach and analysis of its association with outcome in ovarian cancer patients. Clin Cancer Res 2011;17(16):5490–500. doi: 10.1158/1078-0432.CCR-11-0724
  14. Meng Q.H., Xu E., Hildebrandt M.A.T. et al. Genetic variants in the fibroblast growth factor pathway as potential markers of ovarian cancer risk, therapeutic response, and clinical outcome. Clin Chem 2014;60(1):222–32. doi: 10.1373/clinchem.2013.211490
  15. Permuth-Wey J., Fulp W.J., Reid B.M. et al. STAT3 polymorphisms may predict an unfavorable response to first-line platinum-based therapy for women with advanced serous epithelial ovarian cancer. Int J Cancer 2016;138(3):612–9. doi: 10.1002/ijc.29799
  16. Quintanilha J.C.F., Wang J., Sibley A.B. et al. Genome-wide association studies of survival in 1520 cancer patients treated with bevacizumab-containing regimens. Int J Cancer 2022;150(2):279–89. doi: 10.1002/ijc.33810
  17. Fiszer-Maliszewska Ł., Łaczmański Ł., Dolińska A. et al. Polymorphisms of ABCB1, CYP3A4 and CYP3A5 genes in ovarian cancer and treatment response in poles. Anticancer Res 2018;38(3):1455–9. doi: 10.21873/anticanres.12370
  18. Kang S., Ju W., Kim J.W. et al. Association between excision repair cross-complementation group 1 polymorphism and clinical outcome of platinum-based chemotherapy in patients with epithelial ovarian cancer. Exp Mol Med 2006;38(3):320–4. doi: 10.1038/emm.2006.38
  19. Tang N., Lyu D., Zhang Y., Liu H. Association betweeфn the ERCC1 polymorphism and platinum-based chemotherapy effectiveness in ovarian cancer: a meta-analysis. BMC Womens Health 2017;17(1):43. doi: 10.1186/s12905-017-0393-z
  20. Xu M., Liu Y., Li D. et al. Chinese C allele carriers of the ERCC5 rs17655 polymorphism are more sensitive to platinum-based chemotherapy: a meta-analysis. Oncotarget 2017;9(1):1248–56. doi: 10.18632/oncotarget.18981
  21. Zhao J., Wu J., Zuo W. et al. A functional polymorphism in the poly(ADP-ribose) polymerase-1 gene is associated with platinum-based chemotherapeutic response and prognosis in epithelial ovarian cancer patients. Eur J Obstet Gynecol Reprod Biol 2020;255:183–9. doi: 10.1016/j.ejogrb.2020.10.021
  22. McGuire W.P., Hoskins W.J., Brady M.F. et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334(1):1–6. doi: 10.1056/NEJM199601043340101
  23. Burger H., Loos W.J., Eechoute K. et al. Drug transporters of platinum-based anticancer agents and their clinical significance. Drug Resist Updat 2011;14(1):22–34. doi: 10.1016/j.drup.2010.12.002
  24. Howell S.B., Safaei R., Larson C.A., Sailor M.J. Copper transporters and the cellular pharmacology of the platinum-containing cancer drugs. Mol Pharmacol 2010;77(6):887–94. doi: 10.1124/mol.109.063172
  25. Beretta G.L., Gatti L., Tinelli S. et al. Cellular pharmacology of cisplatin in relation to the expression of human copper transporter CTR1 in different pairs of cisplatin-sensitive and -resistant cells. Biochem Pharmacol 2004;68(2):283–91. doi: 10.1016/j.bcp.2004.03.022
  26. Ishida S., Lee J., Thiele D.J., Herskowitz I. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci USA 2002;99(22):14298–302. doi: 10.1073/pnas.162491399
  27. Xie K., Doles J., Hemann M.T., Walker G.C. Error-prone translesion synthesis mediates acquired chemoresistance. Proc Natl Acad Sci USA 2010;107(48):20792–97. doi: 10.1073/pnas.1011412107
  28. Lin J., Li A., Liu L. et al. Platinum-resistant ovarian cancer in China: practice and challenges. Chin Med J (Engl) 2026;139(1):4–6. doi: 10.1097/CM9.0000000000003763
  29. Markman M., Rothman R., Hakes T. et al. Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 1991;9(3):389–93. doi: 10.1200/JCO.1991.9.3.389
  30. Pujade-Lauraine E., Banerjee S., Pignata S. Management of platinum-resistant, relapsed epithelial ovarian cancer and new drug perspectives. J Clin Oncol 2023;41(19):3503–14. doi: 10.1200/JCO.22.02833
  31. Friedlander M., Trimble E., Tinker A. et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 2011;21(4):771–5. doi: 10.1097/IGC.0b013e31821bb8be
  32. Vergote I., Gonzalez-Martin A., Lorusso D. et al. Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup. Lancet Oncol 2022;23(8):e374–84. doi: 10.1016/S1470-2045(22)00139-5
  33. Trillsch F., Mahner S., Czogalla B. et al. Primary platinum resistance and its prognostic impact in patients with recurrent ovarian cancer: an analysis of three prospective trials from the NOGGO study group. J Gynecol Oncol 2021;32(3):e37. doi: 10.3802/jgo.2021.32.e37
  34. Davis A., Tinker A.V., Friedlander M. “Platinum resistant” ovarian cancer: What is it, who to treat and how to measure benefit? Gynecol Oncol 2014;133(3):624–31. doi: 10.1016/j.ygyno.2014.02.038
  35. Miras I., Estevez-García P., Muñoz-Galván S. Clinical and molecular features of platinum resistance in ovarian cancer. Crit Rev Oncol Hematol 2024;201:104434. doi: 10.1016/j.critrevonc.2024.104434
  36. Blair B.G., Larson C.A., Adams P.L. et al. Copper transporter 2 regulates endocytosis and controls tumor growth and sensitivity to cisplatin in vivo. Mol Pharmacol 2011;79(1):157–66. doi: 10.1124/mol.110.068411
  37. Lee Y.Y., Choi C.H., Do I.G. et al. Prognostic value of the copper transporters, CTR1 and CTR2, in patients with ovarian carcinoma receiving platinum-based chemotherapy. Gynecol Oncol 2011;122(2):361–5. doi: 10.1016/j.ygyno.2011.04.025
  38. Nakayama K., Kanzaki A., Ogawa K. et al. Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP. Int J Cancer 2002;101(5):488–95. doi: 10.1002/ijc.10608
  39. Abakumova T.V., Gening S.O., Fedotova A.Yu. et al. Glutathione system in patients with ovarian cancer during chemotherapy according to the AR regimen. Ulianovskiy mediko-biologicheskiy zhurnal = Ulyanovsk Medical and Biological Journal 2018;(3):44–52. (In Russ.). doi: 10.23648/UMBJ.2018.31.17181
  40. Hamada S.I., Kamada M., Furumoto H. et al. Expression of glutathione S-transferase-π in human ovarian cancer as an indicator of resistance to chemotherapy. Gynecol Oncol 1994;52(3):313–9. doi: 10.1006/gyno.1994.1055
  41. Alsheikh B., Attar R., Güleç Yilmaz S. et al. The role of GPX1 (rs1050450) variants in ovarian cancer susceptibility within a turkish population. Cancer Control 2025;32:10732748251332441. doi: 10.1177/10732748251332441
  42. Kuo M.T., Chen H.H., Song I.S. et al. The roles of copper transporters in cisplatin resistance. Cancer Metastasis Rev 2007;26(1):71–83. doi: 10.1007/s10555-007-9045-3
  43. Kiss R.C., Xia F., Acklin S. Targeting DNA damage response and repair to enhance therapeutic index in cisplatin-based cancer treatment. Int J Mol Sci 2021;22(15):8199. doi: 10.3390/ijms22158199
  44. Kothandapani A., Dangeti V.S., Brown A.R. et al. Novel role of base excision repair in mediating cisplatin cytotoxicity. J Biol Chem 2011;286(16):14564–74. doi: 10.1074/jbc.M111.225375
  45. Smolarz B., Makowska M., Samulak D. et al. Single nucleotide polymorphisms (SNPs) of ERCC2, hOGG1, and XRCC1 DNA repair genes and the risk of triple-negative breast cancer in Polish women. Tumour Biol 2014;35(4):3495–502. doi: 10.1007/s13277-013-1461-0
  46. Saldivar J.S., Lu K.H., Liang D. et al. Moving toward individualized therapy based on NER polymorphisms that predict platinum sensitivity in ovarian cancer patients. Gynecol Oncol 2007;107(Suppl 1):S223–9. doi: 10.1016/j.ygyno.2007.07.024
  47. Zavarykina T., Kapralova M., Lomskova P. et al. The association of rs25487 of the XRCC1 gene and rs13181 of the ERCC2 gene polymorphisms with the ovarian cancer risk. Biomol Biomed 2025;25(5):1197–204. doi: 10.17305/bb.2024.11314
  48. Steffensen K.D., Waldstrøm M., Jakobsen A. DNA-repair ERCC1 gene polymorphisms in epithelial ovarian cancer and relation to platinum resistance and survival. J Cancer Ther 2011;2(2):140–7.doi: 10.4236/jct.2011.22016
  49. Bösmüller H., Haitchi-Petnehazy S., Webersinke G. et al. Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy. Virchows Arch 2011;459(2):183–91.doi: 10.1007/s00428-011-1110-1
  50. White K.L., Vierkant R.A., Fogarty Z.C. et al. Analysis of over 10,000 cases finds no association between previously reported candidate polymorphisms and ovarian cancer outcome. Cancer Epidemiol Biomarkers Prev 2013;22(5):987–92. doi: 10.1158/1055-9965.EPI-13-0028
  51. Zhang Y., Cao S., Zhuang C. et al. ERCC1 rs11615 polymorphism and chemosensitivity to platinum drugs in patients with ovarian cancer: a systematic review and meta-analysis. J Ovarian Res 2021;14(1):80. doi: 10.1186/s13048-021-00831-y
  52. Kirschner K., Melton D.W. Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. Anticancer Res 2010;30(9):3223–32.
  53. Valova Ya.V., Mingazheva E.T., Prokofyeva D.S. et al. The role of polymorphic variants of the ERCC2 excision repair gene in the pathogenesis of ovarian cancer in women of different ethnic origins. Geny i kletki = Genes & Cells 2022;17(2):55–9. (In Russ.).
  54. Nosho K., Yamamoto H., Mikami M. et al. Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis. Eur J Cancer 2006;42(14):2374–81. doi: 10.1016/j.ejca.2006.01.061
  55. Armstrong D.K., Alvarez R.D., Bakkum-Gamez J.N. et al. Ovarian cancer, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2021;19(2):191–226. doi: 10.6004/jnccn.2021.0007
  56. Cole C., Lau S., Backen A. et al. Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer. Cancer Biol Ther 2010;10(5):495–504. doi: 10.4161/cbt.10.5.12585
  57. Arend R.C., Londono-Joshi A.I., Straughn J.M. Jr, Buchsbaum D.J. The Wnt/beta-catenin pathway in ovarian cancer: a review. Gynecol Oncol 2013;131(3):772–9. doi: 10.1016/j.ygyno.2013.09.034
  58. Kovalev O.I. Stem cell properties of cancer cells in ascitic fluid of patients with ovarian cancer: a key to control over cancer progression. Byulleten’ sibirskoy meditsiny = Bulletin of Siberian Medicine 2023;22(2):122–33. (In Russ.).
  59. Chang B., Liu G., Xue F. et al. ALDH1 expression correlates with favorable prognosis in ovarian cancers. Mod Pathol 2009;22(6):817–23. doi: 10.1038/modpathol.2009.39
  60. Li Y., Yang S.Y., Kang S. et al. Association between polymorphisms of ERCC1 and survival in epithelial ovarian cancer patients with chemotherapy. Pharmacogenomics 2012;13(4):419–27. doi: 10.2217/pgs.11.181
  61. Yang F., Mu X., Bian C. et al. Association of excision repair cross-complimentary group 1 gene polymorphisms with breast and ovarian cancer susceptibility. J Cell Biochem 2019;120(9):15635–47.doi: 10.1002/jcb.28830

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2026 ABV-Press

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-57560 от  08.04.2014.