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Homologous recombination deficiency (HRD) signature-3 in ovarian and uterine carcinosarcomas correlates with preclinical sensitivity to Olaparib, a poly (adenosine diphosphate [ADP]- ribose) polymerase (PARP) inhibitor

      Highlights

      • Signature-3 (i.e. HRD-related signature) was identified in 60% of OCS (15 of 25) vs 25% of UCS (12 of 48) (p = 0.005).
      • Carcinosarcoma cell lines with HRD signature-3 are significantly more sensitive to treatment with olaparib.
      • Olaparib significantly impaired HRD CS xenografts tumor growth (p = 0.0008) and increased overall survival (p < 0.0001).
      • Clinical studies with PARP inhibitors in CS patients with a dominant signature 3 (HRD-related) are warranted.

      Abstract

      Objectives

      Carcinosarcoma (CS) of the ovary and uterus are highly aggressive malignancies associated with poor survival. Poly(ADP-ribose)-polymerase inhibitors (PARPi) are targeted agents impairing DNA repair via homologous-recombination-deficiency (HRD) mechanisms. We used whole-exome-sequencing (WES) data from a cohort of fresh tumor samples of ovarian (OCS) and uterine carcinosarcoma (UCS), primary cell lines and xenografts to investigate the role for olaparib in CSs.

      Methods

      WES data from 73 CS samples (48 UCS and 25 OCS) were analyzed for HRD signatures. Olaparib activity was evaluated using cell-viability, cell-cycle, apoptosis and cytotoxicity assays against primary CS cell lines. Olaparib antitumor activity was tested in vivo against HRD CS xenografts.

      Results

      Signature-3 (i.e. HRD-related signature) was identified in 60% of OCS (15 of 25) vs 25% of UCS (12 of 48) (p = 0.005). CS cell lines harboring Signature-3/HRD (3 OCS/1 UCS) were significantly more sensitive to olaparib when compared to HRP cell lines (5 UCS/1 OCS) [mean IC50 ± SEM = 2.94 μM ± 0.07 vs mean ± SEM = 23.3 μM ± 0.09, (p = 0.02), respectively]. PARPi suppressed CS cell growth through cell cycle arrest in the G2/M phase and caused more apoptosis in HRD vs HRP primary tumors (p < 0.0001). In vivo, olaparib significantly impaired HRD CS xenografts tumor growth (p = 0.0008) and increased overall animal survival (p < 0.0001).

      Conclusions

      OCS and UCS cell lines harboring HRD signature-3 were significantly more sensitive to olaparib in vitro and in vivo when compared to HRP CS. Clinical studies with PARPi in CS patients with a dominant signature 3 (HRD-related) are warranted.

      Keywords

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      References

        • Siegel R.L.
        • Miller K.D.
        • Fuchs H.E.
        • Jemal A.
        Cancer statistics, 2021.
        CA Cancer J. Clin. 2021; 2021: 7-33
        • Artioli G.
        • Wabersich J.
        • Ludwig K.
        • Gardiman M.P.
        • Borgato L.
        • Garbin F.
        Rare uterine cancer: carcinosarcomas. Review from histology to treatment.
        Crit. Rev. Oncol. Hematol. 2015; 94: 98-104
        • Zhao S.
        • Bellone S.
        • Lopez S.
        • Thakral D.
        • Schwab C.
        • English D.P.
        • Black J.
        • Cocco E.
        • Choi J.
        • Zammataro L.
        • Predolini F.
        • Bonazzoli E.
        • Bi M.
        • Buza N.
        • Hui P.
        • Wong S.
        • Abu-Khalaf M.
        • Ravaggi A.
        • Bignotti E.
        • Bandiera E.
        • Romani C.
        • Todeschini P.
        • Tassi R.
        • Zanotti L.
        • Odicino F.
        • Pecorelli S.
        • Donzelli C.
        • Ardighieri L.
        • Facchetti F.
        • Falchetti M.
        • Silasi D.A.
        • Ratner E.
        • Azodi M.
        • Schwartz P.E.
        • Mane S.
        • Angioli R.
        • Terranova C.
        • Quick C.M.
        • Edraki B.
        • Bilgüvar K.
        • Lee M.
        • Choi M.
        • Stiegler A.L.
        • Boggon T.J.
        • Schlessinger J.
        • Lifton R.P.
        • Santin A.D.
        Mutational landscape of uterine and ovarian carcinosarcomas implicates histone genes in epithelial-mesenchymal transition.
        Proc. Natl. Acad. Sci. U. S. A. 2016 Oct 25; 113 (Epub 2016 Oct 10. PMID: 27791010): 12238-12243
        • Travaglino A.
        • Raffone A.
        • Gencarelli A.
        • Mollo A.
        • Guida M.
        • Insabato L.
        • Santoro A.
        • Zannoni G.F.
        • Zullo F.
        TCGA classification of endometrial cancer: the place of carcinosarcoma.
        Pathol. Oncol. Res. 2020; 26: 2067-2073
        • Garg G.
        • Shah J.P.
        • Kumar S.
        • Bryant C.S.
        • Munkarah A.
        • Morris R.T.
        Ovarian and uterine carcinosarcomas: a comparative analysis of prognostic variables and survival outcomes.
        Int. J. Gynecol. Cancer. 2010; 20: 888-894
        • Alexandrov L.B.
        • Nik-Zainal S.
        • Wedge D.C.
        • et al.
        Signatures of mutational processes in human cancer [published correction appears in nature. 2013 Oct 10;502(7470):258. Imielinsk, Marcin [corrected to Imielinski, Marcin]].
        Nature. 2013; 500: 415-421https://doi.org/10.1038/nature12477
        • Alexandrov L.B.
        • Kim J.
        • Haradhvala N.J.
        • et al.
        The repertoire of mutational signatures in human cancer.
        Nature. 2020; 578: 94-101https://doi.org/10.1038/s41586-020-1943-3
        • Zimmer A.S.
        • Gillard M.
        • Lipkowitz S.
        • Lee J.M.
        Update on PARP inhibitors in breast Cancer.
        Curr. Treat. Options in Oncol. 2018; 19: 21
        • Fong P.C.
        • Yap T.A.
        • Boss D.S.
        • Carden C.P.
        • Mergui-Roelvink M.
        • Gourley C.
        • et al.
        Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.
        J. Clin. Oncol. 2010; 28: 2512-2519
        • Slade D.
        PARP and PARG inhibitors in cancer treatment.
        Genes Dev. 2020; 34: 360-394https://doi.org/10.1101/gad.334516.119
        • Rouleau M.
        • Patel A.
        • Hendzel M.J.
        • Kaufmann S.H.
        • Poirier G.G.
        PARP inhibition: PARP1 and beyond.
        Nat. Rev. Cancer. 2010; 10: 293-301https://doi.org/10.1038/nrc2812
        • McKenna A.
        • Hanna M.
        • Banks E.
        • Sivachenko A.
        • Cibulskis K.
        • Kernytsky A.
        • Garimella K.
        • Altshuler D.
        • Gabriel S.
        • Daly M.
        • DePristo M.A.
        The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.
        Genome Res. 2010; 20: 1297-1303
        • Van der Auwera G.A.
        • O’Connor B.D.
        Genomics in the Cloud: Using Docker, GATK, and WDL in Terra.
        1st ed. O’Reilly Media, 2020
        • Shen R.
        • Seshan V.E.
        FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing.
        Nucleic Acids Res. 2016 Sep 19; 44 (Epub 2016 Jun 7. PMID: 27270079; PMCID: PMC5027494): e131https://doi.org/10.1093/nar/gkw520
        • Mermel C.H.
        • Schumacher S.E.
        • Hill B.
        • Meyerson M.L.
        • Beroukhim R.
        • Getz G.
        GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers.
        Genome Biol. 2011; 12 (Epub 2011 Apr 28): R41https://doi.org/10.1186/gb-2011-12-4-r41
        • Li Charles
        • Bonazzoli Elena
        • Bellone Stefania
        • et al.
        Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors.
        Proc. Natl. Acad. Sci. U. S. A. 2019 Jan 8; 116 (Correction in: Proc Natl Acad Sci U S A. 2019 Mar 19; 116(12): 5829.PMCID: PMC6329978): 619-624https://doi.org/10.1073/pnas.1814027116
        • Zhao Siming
        • Choi Murim
        • Overton John D.
        • et al.
        Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma.
        Proc. Natl. Acad. Sci. U. S. A. 2013 Feb 19; 110: 2916-2921https://doi.org/10.1073/pnas.1222577110. PMCID: PMC3581983
        • Bellone S.
        • Roque D.
        • Siegel E.
        • et al.
        A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus MLH-1 methylated characteristics.
        NCT02899793. 2021; 32: 1045-1046https://doi.org/10.1016/j.annonc.2021.04.013
        • Bellone S.
        • Roque D.M.
        • Siegel E.R.
        • Buza N.
        • Hui P.
        • Bonazzoli E.
        • Guglielmi A.
        • Zammataro L.
        • Nagarkatti N.
        • Zaidi S.
        • Lee J.
        • Silasi D.A.
        • Huang G.S.
        • Andikyan V.
        • Damast S.
        • Clark M.
        • Azodi M.
        • Schwartz P.E.
        • Tymon-Rosario J.R.
        • Harold J.A.
        • Mauricio D.
        • Zeybek B.
        • Menderes G.
        • Altwerger G.
        • Ratner E.
        • Alexandrov L.B.
        • Iwasaki A.
        • Kong Y.
        • Song E.
        • Dong W.
        • Elvin J.A.
        • Choi J.
        • Santin A.D.
        A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability.
        Cancer. 2021 Dec 7; (Online ahead of print.PMID: 34875107)https://doi.org/10.1002/cncr.34025
        • Charles W.A.
        • Arnaud Da Cruz P.
        • Rahul K.
        • et al.
        Analysis of mutational signatures in primary and metastatic endometrial cancer reveals distinct patterns of DNA repair defects and shifts during tumor progression.
        Gynecol. Oncol. 2019 Jan; 152: 11-19https://doi.org/10.1016/j.ygyno.2018.10.032
        • Resnick E.
        • Taxy J.B.
        Neoadjuvant chemotherapy in uterine papillary serous carcinoma.
        Gynecol. Oncol. 1996; 62: 123-127
        • Rauh-Hain J.A.
        • Diver E.J.
        • Clemmer J.T.
        • et al.
        Carcinosarcoma of the ovary compared to papillary serous ovarian carcinoma: a SEER analysis.
        Gynecol. Oncol. 2013; 131: 46-51
        • Kalil N.G.
        • McGuire W.P.
        Chemotherapy for advanced epithelial ovarian carcinoma.
        Best Pract. Res. Clin. Obstet. Gynaecol. 2002; 16: 553-557
        • Levenback C.
        • Burke T.W.
        • Silva E.
        • Morris M.
        • Gershenson D.M.
        • Kavanagh J.J.
        • Wharton J.T.
        Uterine papillary serous carcinoma (USPC) treated with cisplatin, doxorubicin, and cyclophosphamide (PAC).
        Gynecol. Oncol. 1992; 46: 317-321
      1. Lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations.
        Cell Cycle. 2011; 10: 1192-1199
        • Kim G.
        • Ison G.
        • McKee A.E.
        • Zhang H.
        • Tang S.
        • Gwise T.
        • et al.
        FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian Cancer treated with three or more lines of chemotherapy.
        Clin. Cancer Res. 2015; 21: 4257-4261