Targeting synthetic lethality: an effective therapeutic approach in ovarian and endometrial cancers.

[en] Synthetic lethality (SL) is a promising therapeutic concept that relies on the indirect targeting of vulnerabilities acquired through genetic mutations. Ovarian and endometrial cancers frequently exhibit mutations in the breast cancer (BRCA), phosphatase and tensin homolog (PTEN), AT-rich interactive domain-containing protein 1A (ARID1A) and TP53 genes, as well as DNA repair pathway deficiencies. Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated remarkable efficacy in various cancers with BRCA mutations and homologous recombination deficiency. In addition to PARPi, there has been an expansion of drugs exploiting the selective vulnerability of cancer cells via SL, such as WEE1 kinase and Ataxia Telangiectasia and Rad3-related protein (ATR). WEE1 inhibitors have shown encouraging results in combination with chemotherapy, increasing the objective response rate in patients with platinum-resistant TP53-mutated ovarian cancer. ATR inhibitors are currently being evaluated in ARID1A-mutated tumours, with preliminary results confirming their therapeutic potential.

Disciplines :

Oncology

Author, co-author :

Lebeau, Alizée ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale

Kakkos, Athanasios ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gynécologie-obstétrique

LEROI, Natacha ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique

Bours, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique

Delbecque, Katty ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques

Goffin, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gynécologie-obstétrique

Gonne, Elodie ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale

Gennigens, Christine ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale

Language :

English

Title :

Targeting synthetic lethality: an effective therapeutic approach in ovarian and endometrial cancers.

Publication date :

05 December 2025

Journal title :

Therapeutic Advances in Medical Oncology

ISSN :

1758-8340

eISSN :

1758-8359

Publisher :

SAGE Publications, England

Volume :

Pages :

17588359251392106

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://journals.sagepub.com/doi/pdf/10.1177/17588359251392106

Funders :

CHU Liège - Centre Hospitalier Universitaire de Liège

Funding text :

Department of Medical Oncology at CHU de Liège

Available on ORBi :

since 12 January 2026

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Bibliography

Levine DA. Integrated genomic characterization of endometrial carcinoma. Nature 2013; 497(7447): 67–73.
Bell D, Berchuck A, Birrer M, et al. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474(7353): 609–615.
Wiegand KC, Shah SP, Al-Agha OM, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010; 363(16): 1532–1543.
Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol 2014; 25(1): 32–40.
Williamson CT, Miller R, Pemberton HN, et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat Commun 2016; 7: 13837.
Salmon A, Lebeau A, Streel S, et al. Locally advanced and metastatic endometrial cancer: current and emerging therapies. Cancer Treat Rev 2024; 129: 102790.
Truesdell P, Chang J, Coto Villa D, et al. Pharmacogenomic discovery of genetically targeted cancer therapies optimized against clinical outcomes. NPJ Precis Oncol 2024; 8(1): 1–13.
Hunter P. Understanding redundancy and resilience. EMBO Rep 2022; 23(3): e54742.
Zhang B, Tang C, Yao Y, et al. The tumor therapy landscape of synthetic lethality. Nat Commun 2021; 12(1): 1275.
O’Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer. Nat Rev Genet 2017; 18(10): 613–623.
Hartwell LH, Szankasi P, Roberts CJ, et al. Integrating genetic approaches into the discovery of anticancer drugs. Science 1997; 278(5340): 1064–1068.
Kaelin WG. Choosing anticancer drug targets in the postgenomic era. J Clin Invest 1999; 104(11): 1503–1506.
Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434(7035): 913–917.
Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434(7035): 917–921.
Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361(2): 123–134.
Chen H, Liu H, Qing G. Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduct Target Ther 2018; 3: 5.
Goga A, Yang D, Tward AD, et al. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat Med 2007; 13(7): 820–827.
Kang J, Sergio CM, Sutherland RL, et al. Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells. BMC Cancer 2014; 14: 32.
Höglund A, Nilsson LM, Muralidharan SV, et al. Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells. Clin Cancer Res 2011; 17(22): 7067–7079.
Dominguez-Sola D, Ying CY, Grandori C, et al. Non-transcriptional control of DNA replication by c-Myc. Nature 2007; 448(7152): 445–451.
Murga M, Campaner S, Lopez-Contreras AJ, et al. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol 2011; 18(12): 1331–1335.
Ku AA, Hu HM, Zhao X, et al. Integration of multiple biological contexts reveals principles of synthetic lethality that affect reproducibility. Nat Commun 2020; 11: 2375.
Bindra RS, Schaffer PJ, Meng A, et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 2004; 24(19): 8504–8518.
Chan N, Koritzinsky M, Zhao H, et al. Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Res 2008; 68(2): 605–614.
Lu Y, Chu A, Turker MS, et al. Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol Cell Biol 2011; 31(16): 3339–3350.
Chan N, Pires IM, Bencokova Z, et al. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res 2010; 70(20): 8045–8054.
Jung AC, Guihard S, Krugell S, et al. CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis. Int J Cancer 2013; 132(2): E26–E36.
Kimple RJ, Smith MA, Blitzer GC, et al. Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res 2013; 73(15): 4791–4800.
Bruyere D, Roncarati P, Lebeau A, et al. Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair. Theranostics 2023; 13(3): 1130–1149.
Mann M, Singh VP, Kumar L. Cervical cancer: a tale from HPV infection to PARP inhibitors. Genes Dis 2022; 10(4): 1445–1456.
Ryan CJ, Devakumar LPS, Pettitt SJ, et al. Complex synthetic lethality in cancer. Nat Genet 2023; 55(12): 2039–2048.
Voutsadakis IA. KRAS mutated colorectal cancers with or without PIK3CA mutations: clinical and molecular profiles inform current and future therapeutics. Crit Rev Oncol Hematol 2023; 186: 103987.
Dankort D, Curley DP, Cartlidge RA, et al. BRafV600E cooperates with Pten silencing to elicit metastatic melanoma. Nat Genet 2009; 41(5): 544–552.
Chandler RL, Damrauer JS, Raab JR, et al. Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signaling. Nat Commun 2015; 6: 6118.
Bunting SF, Callén E, Wong N, et al. 53BP1 inhibits homologous recombination in brca1-deficient cells by blocking resection of DNA breaks. Cell 2010; 141(2): 243–254.
Gogola E, Duarte AA, de Ruiter JR, et al. Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell 2018; 33(6): 1078.e12–1093.e12.
Tang S, Gökbağ B, Fan K, et al. Synthetic lethal gene pairs: experimental approaches and predictive models. Front Genet 2022; 13: 961611.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646–674.
Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov 2022; 12(1): 31–46.
Huang R, Zhou PK. DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct Target Ther 2021; 6(1): 1–35.
Prakash A, Doublié S. Base excision repair in the mitochondria. J Cell Biochem 2015; 116(8): 1490–1499.
Marteijn JA, Lans H, Vermeulen W, et al. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol 2014; 15(7): 465–481.
Chang HHY, Pannunzio NR, Adachi N, et al. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol 2017; 18(8): 495–506.
Beinse G, Just PA, Le Frere Belda MA, et al. Discovery and validation of a transcriptional signature identifying homologous recombination-deficient breast, endometrial and ovarian cancers. Br J Cancer 2022; 127(6): 1123–1132.
Konstantinopoulos PA, Ceccaldi R, Shapiro GI, et al. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 2015; 5(11): 1137–1154.
Takamatsu S, Yoshihara K, Baba T, et al. Prognostic relevance of HRDness gene expression signature in ovarian high-grade serous carcinoma; JGOG3025-TR2 study. Br J Cancer 2023; 128(6): 1095–1104.
de Jonge MM, Auguste A, van Wijk LM, et al. Frequent homologous recombination deficiency in high-grade endometrial carcinomas. Clin Cancer Res 2019; 25(3): 1087–1097.
Scully R, Panday A, Elango R, et al. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat Rev Mol Cell Biol 2019; 20(11): 698–714.
Pettitt SJ, Krastev DB, Brandsma I, et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun 2018; 9(1): 1849.
Noordermeer SM, van Attikum H. PARP inhibitor resistance: a tug-of-war in BRCA-mutated cells. Trends Cell Biol 2019; 29(10): 820–834.
Ganesan S. Tumor suppressor tolerance: reversion mutations in BRCA1 and BRCA2 and resistance to PARP inhibitors and platinum. JCO Precis Oncol 2018; 2: 1–4.
Du Y, Yamaguchi H, Wei Y, et al. Blocking c-Met–mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nat Med 2016; 22(2): 194–201.
Tapodi A, Debreceni B, Hanto K, et al. Pivotal role of Akt activation in mitochondrial protection and cell survival by poly(ADP-ribose)polymerase-1 inhibition in oxidative stress. J Biol Chem 2005; 280(42): 35767–35775.
Haynes B, Murai J, Lee JM. Restored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition. Cancer Treat Rev 2018; 71: 1.
Kim H, George E, Ragland RL, et al. Targeting the ATR/CHK1 axis with PARP inhibition results in tumor regression in BRCA-mutant ovarian cancer models. Clin Cancer Res 2017; 23(12): 3097–3108.
Kim H, Xu H, George E, et al. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun 2020; 11(1): 3726.
Biegała Ł, Gajek A, Szymczak-Pajor I, et al. Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2MUT ovarian cancer cells. Sci Rep 2023; 13(1): 22659.
Ngoi NYL, Pilié PG, McGrail DJ, et al. Targeting ATR in patients with cancer. Nat Rev Clin Oncol 2024; 21(4): 278–293.
Wu JN, Roberts CWM. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Discov 2013; 3(1): 35–43.
Guan B, Wang TL, Shih IM. ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res 2011; 71(21): 6718.
Jones S, Wang TL, Shih IM, et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 2010; 330(6001): 228–231.
Wilson BG, Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11(7): 481–492.
Shen J, Peng Y, Wei L, et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov 2015; 5(7): 752–767.
Bakr A, Corte GD, Veselinov O, et al. ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response. Nucleic Acids Res 2024; 52(10): 5698–5719.
Dykhuizen EC, Hargreaves DC, Miller EL, et al. BAF complexes facilitate decatenation of DNA by topoisomerase IIα. Nature 2013; 497(7451): 624–627.
Tsai S, Fournier LA, Chang EYC, et al. ARID1A regulates R-loop associated DNA replication stress. PLoS Genet 2021; 17(4): e1009238.
Allo G, Bernardini MQ, Wu RC, et al. ARID1A loss correlates with mismatch repair deficiency and intact p53 expression in high-grade endometrial carcinomas. Mod Pathol 2014; 27(2): 255–261.
Bitler BG, Aird KM, Garipov A, et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat Med 2015; 21(3): 231–238.
Mandal J, Mandal P, Wang TL, et al. Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response. J Biomed Sci 2022; 29: 71.
Rehman H, Chandrashekar DS, Balabhadrapatruni C, et al. ARID1A-deficient bladder cancer is dependent on PI3K signaling and sensitive to EZH2 and PI3K inhibitors. JCI Insight 2022; 7(16): e155899.
Samartzis EP, Noske A, Dedes KJ, et al. ARID1A mutations and PI3K/AKT pathway alterations in endometriosis and endometriosis-associated ovarian carcinomas. Int J Mol Sci 2013; 14(9): 18824–18849.
Zeng J, Hills SA, Ozono E, et al. Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication. Cell 2023; 186(3): 528.e14–542.e14.
Bacˇević K, Lossaint G, Achour TN, et al. Cdk2 strengthens the intra-S checkpoint and counteracts cell cycle exit induced by DNA damage. Sci Rep 2017; 7(1): 13429.
Wang H, Guo M, Wei H, et al. Targeting p53 pathways: mechanisms, structures and advances in therapy. Signal Transduct Target Ther 2023; 8(1): 1–35.
Aubrey BJ, Kelly GL, Janic A, et al. How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death Differ 2018; 25(1): 104–113.
Tuna M, Ju Z, Yoshihara K, et al. Clinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers. Br J Cancer 2020; 122(3): 405–412.
Schultheis AM, Martelotto LG, De Filippo MR, et al. TP53 mutational spectrum in endometrioid and serous endometrial cancers. Int J Gynecol Pathol 2016; 35(4): 289–300.
Wang Z, Li W, Li F, et al. An update of predictive biomarkers related to WEE1 inhibition in cancer therapy. J Cancer Res Clin Oncol 2024; 150(1): 13.
Reinhardt HC, Aslanian AS, Lees JA, et al. P53-Deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 2007; 11(2): 175–189.
Reaper PM, Griffiths MR, Long JM, et al. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 2011; 7(7): 428–430.
Jiang H, Reinhardt HC, Bartkova J, et al. The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev 2009; 23(16): 1895–1909.
Qiu Z, Oleinick NL, Zhang J. ATR/CHK1 inhibitors and cancer therapy. Radiother Oncol 2018; 126(3): 450–464.
Fagundes R, Teixeira LK. Cyclin E/CDK2: DNA replication, replication stress and genomic instability. Front Cell Dev Biol 2021; 9: 774845.
Karst AM, Jones PM, Vena N, et al. Cyclin E1 deregulation occurs early in secretory cell transformation to promote formation of fallopian tube-derived high-grade serous ovarian cancers. Cancer Res 2014; 74(4): 1141–1152.
Xu H, George E, Kinose Y, et al. CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models. Cell Rep Med 2021; 2(9): 100394.
Etemadmoghadam D, deFazio A, Beroukhim R, et al. Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemo-resistance in ovarian carcinomas. Clin Cancer Res 2009; 15(4): 1417–1427.
Nakayama N, Nakayama K, Shamima Y, et al. Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer. Cancer 2010; 116(11): 2621–2634.
Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol 2022; 23(1): 74–88.
Minella AC, Grim JE, Welcker M, et al. P53 and SCFFbw7 cooperatively restrain cyclin E-associated genome instability. Oncogene 2007; 26(48): 6948–6953.
Suski JM, Braun M, Strmiska V, et al. Targeting cell-cycle machinery in cancer. Cancer Cell 2021; 39(6): 759–778.
Yang J, Nie J, Ma X, et al. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer 2019; 18(1): 26.
Nero C, Ciccarone F, Pietragalla A, et al. PTEN and gynecological cancers. Cancers 2019; 11(10): 1458.
Mukherjee R, Vanaja KG, Boyer JA, et al. Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis. Mol Cell 2021; 81(4): 708.e5–723.e5.
Sinha A, Saleh A, Endersby R, et al. RAD51-mediated DNA homologous recombination is independent of PTEN mutational status. Cancers 2020; 12(11): 3178.
Diao L, Chen YG. PTEN, a general negative regulator of cyclin D expression. Cell Res 2007; 17(4): 291–292.
Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol 2018; 19(9): 547–562.
Zhao L, Vogt PK. Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci U S A 2008; 105(7): 2652.
Peng Y, Yang Q. Targeting KRAS in gynecological malignancies. FASEB J 2024; 38(19): e70089.
Ledermann JA, Pujade-Lauraine E. Olaparib as maintenance treatment for patients with platinum-sensitive relapsed ovarian cancer. Ther Adv Med Oncol 2019; 11: 1758835919849753.
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016; 375(22): 2154–2164.
Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390(10106): 1949–1961.
Pujade-Lauraine E, Ledermann JA, Selle F, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2017; 18(9): 1274–1284.
Kristeleit R, Lisyanskaya A, Fedenko A, et al. Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial. Lancet Oncol 2022; 23(4): 465–478.
D’Andrea AD. Mechanisms of PARP inhibitor sensitivity and resistance. DNA Repair 2018; 71: 172–176.
DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 trial. J Clin Oncol 2023; 41(3): 609–617.
Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med 2018; 379(26): 2495–2505.
Monk BJ, Barretina-Ginesta MP, Pothuri B, et al. Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial. Ann Oncol 2024; 35(11): 981–992.
Ray-Coquard I, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial. Ann Oncol 2023; 34(8): 681–692.
Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015; 16(8): 928–936.
Lorusso D, Mouret-Reynier MA, Harter P, et al. Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial. Int J Gynecol Cancer 2024; 34(4): 550–558.
Monk BJ, Oaknin A, O’Malley DM, et al. LBA30 ATHENA-COMBO, a phase III, randomized trial comparing rucaparib (RUCA) + nivolumab (NIVO) combination therapy vs RUCA monotherapy as maintenance treatment in patients (pts) with newly diagnosed ovarian cancer (OC). Ann Oncol 2024; 35: S1223–S1224.
O’Malley DM, Oza AM, Lorusso D, et al. Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian carcinoma. Gynecol Oncol 2022; 167(3): 404–413.
Poveda A, Floquet A, Ledermann JA, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2021; 22(5): 620–631.
Mirza MR, Ghamande S, Hanker LC, et al. 38MO progression-free survival (PFS) in primary advanced or recurrent endometrial cancer (pA/rEC) in the overall and mismatch repair proficient (MMR/MSS) populations and in histological and molecular subgroups: results from part 2 of the RUBY trial. ESMO Open 2024; 9: 103538.
Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol 2024; 42(3): 283–299.
Wang C, Li J. Haematologic toxicities with PARP inhibitors in cancer patients: an up‑to‑date meta‑analysis of 29 randomized controlled trials. J Clin Pharm Ther 2021; 46(3): 571–584.
Monk BJ, González-Martin A, Buckley L, et al. Safety and management of niraparib monotherapy in ovarian cancer clinical trials. Int J Gynecol Cancer 2023; 33(6): 971–981.
Vaitsiankova A, Burdova K, Sobol M, et al. PARP inhibition impedes the maturation of nascent DNA strands during DNA replication. Nat Struct Mol Biol 2022; 29(4): 329–338.
Illuzzi G, Staniszewska AD, Gill SJ, et al. Preclinical characterization of AZD5305, a next-generation, highly selective PARP1 inhibitor and trapper. Clin Cancer Res 2022; 28(21): 4724–4736.
Yap TA, Im SA, Schram AM, et al. Abstract CT007: PETRA: first in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations. Cancer Res 2022; 82(12 Suppl): CT007.
Konstantinopoulos PA, da Costa AABA, Gulhan D, et al. A replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer. Nat Commun 2021; 12(1): 5574.
Konstantinopoulos PA, Cheng SC, Lee EK, et al. Randomized phase II study of gemcitabine with or without ATR inhibitor berzosertib in platinum-resistant ovarian cancer: final overall survival and biomarker analyses. JCO Precis Oncol 2024; 8: e2300635.
Simpkins F, Nasioudis D, Wethington SL, et al. Combination ATR and PARP inhibitor (CAPRI): a phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-sensitive epithelial ovarian cancer (cohort A). J Clin Oncol 2024; 42(16 Suppl): 5510.
Wethington SL, Shah PD, Martin L, et al. Combination ATR (ceralasertib) and PARP (olaparib) inhibitor (CAPRI) trial in acquired PARP inhibitor-resistant homologous recombination-deficient ovarian cancer. Clin Cancer Res 2023; 29(15): 2800–2807.
Banerjee S, Stewart J, Porta N, et al. ATARI trial: ATR inhibitor in combination with olaparib in gynecological cancers with ARID1A loss or no loss (ENGOT/GYN1/NCRI). Int J Gynecol Cancer 2021; 31(11): 1471–1475.
Banerjee S, Leary A, Stewart JR, et al. 34O ATR inhibitor alone (ceralasertib) or in combination with olaparib in gynaecological cancers with ARID1A loss or no loss: results from the ENGOT/GYN1/NCRI ATARI trial. ESMO Open 2023; 8(1): 100814.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228–247.
Embaby A, Kutzera J, Geenen JJ, et al. WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer: a biomarker-enriched phase II study. Gynecol Oncol 2023; 174: 239–246.
Lheureux S, Cristea MC, Bruce JP, et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021; 397(10271): 281–292.
Moore KN, Chambers SK, Hamilton EP, et al. Adavosertib with chemotherapy in patients with primary platinum-resistant ovarian, fallopian tube, or peritoneal cancer: an open-label, four-arm, phase II study. Clin Cancer Res 2022; 28(1): 36–44.
Au-Yeung G, Bressel M, Prall O, et al. IGNITE: a phase II signal-seeking trial of adavosertib targeting recurrent high-grade, serous ovarian cancer with cyclin E1 overexpression with and without gene amplification. J Clin Oncol 2022; 40(16 Suppl): 5515.
Oza AM, Estevez-Diz M, Grischke EM, et al. A biomarker-enriched, randomized phase II trial of adavosertib (AZD1775) plus paclitaxel and carboplatin for women with platinum-sensitive TP53-mutant ovarian cancer. Clin Cancer Res 2020; 26(18): 4767–4776.
Westin SN, Coleman RL, Fellman BM, et al. EFFORT: EFFicacy Of adavosertib in parp ResisTance: a randomized two-arm non-comparative phase II study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer. J Clin Oncol 2021; 39(15 Suppl): 5505.
Adjei N, Coleman R, Fellman B, et al. PR072/#1519 effort: clinical and molecular features associated with clinical benefit from adavosertib with or without olaparib in recurrent ovarian cancer following progression on PARP inhibition (NCT03579316). Int J Gynecol Cancer 2023; 33: A71–A73.
Liu JF, Xiong N, Campos SM, et al. Phase II study of the WEE1 inhibitor adavosertib in recurrent uterine serous carcinoma. J Clin Oncol 2021; 39(14): 1531–1539.
Liu J, Oza AM, Colombo N, et al. ADAGIO: a phase IIb international study of the Wee1 inhibitor adavosertib in women with recurrent or persistent uterine serous carcinoma. Int J Gynecol Cancer 2022; 32(1): 89–92.
Liu J, Colombo N, Oza A, et al. ADAGIO: a phase IIb, open-label, single-arm, multicenter study assessing the efficacy and safety of adavosertib (AZD1775) as treatment for recurrent or persistent uterine serous carcinoma (039). Gynecol Oncol 2023; 176: S33–S35.
Liu JF, Fu S, Richardson GE, et al. Correlation of cyclin E1 expression and clinical outcomes in a phase 1b dose-escalation study of azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum-resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC). J Clin Oncol 2023; 41(16 Suppl): 5513.
Sausville E, LoRusso P, Carducci M, et al. Phase I dose-escalation study of AZD7762, a checkpoint kinase inhibitor, in combination with gemcitabine in US patients with advanced solid tumors. Cancer Chemother Pharmacol 2014; 73(3): 539.
Konstantinopoulos PA, Lee JM, Gao B, et al. A phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer. Gynecol Oncol 2022; 167(2): 213.
Lee JM, Nair J, Zimmer A, et al. Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first in class, proof-of-concept, single arm phase 2 study. Lancet Oncol 2018; 19(2): 207.
Kristeleit R, Plummer R, Jones R, et al. A phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer. Br J Cancer 2023; 129(1): 38.
Italiano A, Infante JR, Shapiro GI, et al. Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors. Ann Oncol 2018; 29(5): 1304–1311.
Permata TBM, Hagiwara Y, Sato H, et al. Base excision repair regulates PD-L1 expression in cancer cells. Oncogene 2019; 38(23): 4452–4466.
Du D, Roguev A, Gordon DE, et al. Genetic interaction mapping in mammalian cells using CRISPR interference. Nat Methods 2017; 14(6): 577–580.
Shen JP, Zhao D, Sasik R, et al. Combinatorial CRISPR–Cas9 screens for de novo mapping of genetic interactions. Nat Methods 2017; 14(6): 573–576.