Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press87110.17650/2313-805X-2026-13-3-92-112REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИReview ArticleMolecular mechanisms of resistance to platinum based chemotherapy in serous ovarian cancer: the role of genetic polymorphismМолекулярные механизмы резистентности к платиносодержащей химиотерапии при серозном раке яичников: роль генетического полиморфизмаhttps://orcid.org/0000-0002-0515-5699SubbotinaKristina V.СубботинаКристина Вячеславовна
Russian Federation
ksubbotina01@gmail.comhttps://orcid.org/0000-0001-7805-1914TarkhovA. V.ТарховА. В.
Russian Federation
ksubbotina01@gmail.comhttps://orcid.org/0000-0002-5660-2276BoyarskikhU. A.БоярскихУ. А.
Russian Federation
ksubbotina01@gmail.comhttps://orcid.org/0000-0002-3898-4127KushlinskiiN. E.КушлинскийН. Е.
Russian Federation
ksubbotina01@gmail.comhttps://orcid.org/0000-0002-8950-5368FilipenkoM. L.ФилипенкоМ. Л.
Russian Federation

Institute of Reproductive Genetics

Институт репродуктивной генетики

ksubbotina01@gmail.comInstitute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of SciencesФГБУ «Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук»City Clinical Hospital No. 1, NovosibirskГБУЗ НСО «Городская клиническая больница № 1», НовосибирскN.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава РоссииFederal State Budgetary Institution, National Medical Research Center of Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, Ministry of Health of RussiaФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии им. акад. В.И. Кулакова» Минздрава Россииru220920262026133921121206202622092026Received:12062026Accepted:22092026Published:22092026Copyright ©; 2026, ABV-PressCopyright ©; 2026, АБВ-пресс2026ABV-PressАБВ-прессhttps://creativecommons.org/licenses/by/4.0/https://umo.abvpress.ru/jour/article/view/871

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.

Эпителиальный рак яичников, в первую очередь серозная карцинома высокой степени злокачественности, характеризуется высокой вероятностью возникновения рецидива после первичного лечения – циторедуктивного хирургического вмешательства в сочетании с платиносодержащей химиотерапией. Несмотря на применение стандартных подходов к лечению, показатели бесплатинового интервала, выживаемости без прогрессирования и общей выживаемости существенно варьируются. Помимо соматических особенностей опухоли и полноты циторедукции при хирургическом лечении, вариабельность результатов терапии может определяться герминальным полиморфизмом генов, кодирующих белки, ответственные за транспорт лекарственных препаратов, детоксикацию и репарацию ДНК.

Цель работы – систематизировать данные о молекулярных механизмах чувствительности и резистентности к препаратам платины при серозном раке яичников с акцентом на роль герминальных структурных вариантов ДНК, представить ограничения существующих данных и наметить направления для дальнейших исследований.

Поиск литературы выполнялся в базах данных PubMed, Scopus и Google Scholar по ключевым словам “high-grade serous ovarian cancer”, “platinum”, “carboplatin”, “cisplatin”, “polymorphism”, “SNP”, “pharmacogenetics”, “progression-free survival” и “platinum resistance”. Приоритет отдавался исследованиям с выборкой ≥100 больных раком яичников, а также работам с независимой валидацией и метаанализом. Работы с меньшими выборками были включены в анализ при особой значимости их результатов. Наибольшую воспроизводимость ассоциации с резистентностью к препаратам платины демонстрируют герминальные полиморфизмы генов путей эксцизионной репарации нуклеотидов (ERCC1, ERCC5), транспорта и выведения платины (ABCB1) и отдельных сигнальных путей (STAT3, FGFR4). Многие кандидатные ассоциации остаются противоречивыми из-за вариации определений платинорезистентности, малых выборок, неоднородности по режимам терапии и межэтнических различий в частоте аллелей и эффектах.

serous ovarian cancermechanisms of platinum resistancegenetic polymorphismсерозный рак яичниковмеханизмы платиновой резистентностигенетический полиморфизмМинистерство науки и высшего образования Российской ФедерацииMinistry of Science and Higher Education of the Russian Federation075-03-2025-069The work was performed within the framework of the state assignment of the Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences (No. 125012300674-9).Работа выполнена в рамках государственного задания ФГБУ «Институт химической биологии и фундаментальной медицины Сибирского отделения Российской академии наук» (№ 125012300674-9).Ovarian cancer/fallopian tube cancer/primary peritoneal cancer. Clinical guidelines, Ministry of Health of Russia. Moscow, 2024. (In Russ.).Рак яичников/рак маточной трубы/первичный рак брюшины. Клинические рекомендации Минздрава России. М., 2024.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.xThe 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.).Состояние онкологической помощи населению России в 2023 году. Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2024. 262 c.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.27329Braun 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.0055037Mitamura 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.S387120Konopka 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.11822Moxley 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.2013.04.054Gagno 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.2019.10.019Li 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/bgaa075Li 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.48218Khrunin 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.13.237Huang 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-11-0724Meng 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.2013.211490Permuth-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.29799Quintanilha 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.33810Fiszer-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.12370Kang 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.2006.38Tang 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-zXu 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.18981Zhao 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.2020.10.021McGuire 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/NEJM199601043340101Burger 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.2010.12.002Howell 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.109.063172Beretta 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.2004.03.022Ishida 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.162491399Xie 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.1011412107Lin 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/CM9.0000000000003763Markman 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.1991.9.3.389Pujade-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.22.02833Friedlander 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.0b013e31821bb8beVergote 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)00139-5Trillsch 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.e37Davis 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.2014.02.038Miras 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.2024.104434Blair 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.110.068411Lee 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.2011.04.025Nakayama 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.10608Abakumova 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.2018.31.17181Абакумова Т.В., Генинг С.О., Федотова А.Ю. и др. Система глутатиона у больных раком яичников на фоне химиотерапии по схеме АР. Ульяновский медико-биологический журнал 2018;(3):44–52. DOI: 10.23648/UMBJ.2018.31.17181Hamada 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.1994.1055Alsheikh 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: 10.1177/10732748251332441Kuo 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/s10555-007-9045-3Kiss 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/ijms22158199Kothandapani 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.M111.225375Smolarz 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/s13277-013-1461-0Saldivar 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.2007.07.024Zavarykina 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.2024.11314Steffensen 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.2011.22016Bösmüller 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/s00428-011-1110-1White 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-13-0028Zhang 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-yKirschner 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.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.).Валова Я.В., Мингажева Э.Т., Прокофьева Д.С. и др. Роль полиморфных вариантов гена эксцизионной репарации ERCC2 в патогенезе рака яичников у женщин разного этнического происхождения. Гены и клетки 2022;17(2):56–9Nosho 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.2006.01.061Armstrong 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.2021.0007Cole 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.10.5.12585Arend 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.2013.09.034Kovalev 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.).Ковалев О.И. Стволовые свойства опухолевых клеток асцитической жидкости у больных раком яичника: ключ к управлению распространением процесса. Бюллетень сибирской медицины 2023;22(2):122–33.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.2009.39Li 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.11.181Yang 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