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

Joan R. Tymon-Rosario, Paola Manara, Diego D. Manavella, Stefania Bellone, Tobias Max Philipp Hartwich, Justin Harold, Yang Yang-Hartwich, Margherita Zipponi, Jungmin Choi, Kyungjo Jeong, Levent Mutlu, Kevin Yang, Gary Altwerger, Gulden Menderes, Elena Ratner, Gloria S. Huang, Mitchell Clark, Vaagn Andikyan, Masoud Azodi, Peter E. SchwartzLudmil B. Alexandrov, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)117-125
Number of pages9
JournalGynecologic Oncology
Volume166
Issue number1
DOIs
Publication statusPublished - 2022 Jul

Keywords

  • Carcinosarcoma
  • Homologous-recombination-deficiency (HRD)
  • Poly(ADP-ribose)-polymerase inhibitors (PARPi)
  • Whole-exome-sequencing (WES)

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynaecology

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