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 (043)

Joan Tymon‐Rosario ,Masoud Azodi,Levent Mutlu,Stefania Bellone,Yang Yang-Hartwich,Vaagn Andikyan,Gary Altwerger,Luca Arrigo Zammataro,Elena Ratner,Paola Manara,Gulden Menderes,Justin Harold,Mitchell Clark,Tobias M.p Hartwich ,Eric R Siegel ,Diego Manavella ,Gloria S Huang ,Peter E Schwartz ,Ludmil B Alexandrov ,Alessandro D Santin

doi:10.1016/s0090-8258(22)01262-8

Abstract

Objectives: Carcinosarcoma (CS) of the ovary and uterus are highly aggressive malignancies associated with poor survival. Poly (ADP-ribose)-polymerase (PARP) inhibitors are targeted agents impairing DNA repair via homologous-recombination-deficiency (HRD) mechanisms. We used whole-exome sequencing (WES) data from a large cohort of CS patients to investigate if ovarian carcinosarcoma (OCS) and uterine carcinosarcoma (UCS) possess the mutational signature of homologous recombination deficiency (HRD). The preclinical activity of olaparib in OCS and UCS cell lines and xenograft models were then evaluated. Methods: WES data from 73 CS samples (25 OCS and 48 UCS), including fresh frozen tissues and primary cell lines, were analyzed for HRD signatures as described by Alexandrov et al. (Nature;2020;578:94-101). Olaparib activity on cell cycle, apoptosis, and cytotoxicity was evaluated against ten fully WES primary CS cell lines. Olaparib antitumor activity was tested in vivo against HRD CS xenografts. Results: From a tot al of 73 CS patients, 60% (15 of 25) of OCS versus 17% (13 of 48) of UCS harbored an HRD-related signature (Signature-3), (p<0.002). Of the ten primary fully sequenced CS cell lines, four were HRD (3 OCS vs 1 UCS), and six were HR proficient (HRP) (5 UCS vs 1 OCS). HRD CS cell lines were significantly more sensitive to olaparib when compared to HRP cell lines [mean IC50 ± SEM: 2.94 μM ± 0.07 vs mean ± SEM: 23.3 μM ± 0.09, (p=0.02). In HRD cell lines, olaparib suppressed CS cell growth through cell cycle arrest in the G2/M phase and caused apoptosis (HRD vs HRP (p < 0.0001]). In vivo, olaparib significantly impaired HRD CS xenografts tumor growth (p= 0.001) and increased overall animal survival (p=0.002) (Figure). Conclusions: A large subset of OCS, and to a lower extent, UCS harbor an HRD-related signature. Primary HRD OCS and UCS cell lines are sensitive in vitro and in vivo to olaparib. Clinical studies with PARP inhibitors in CS patients with an HRD signature (Signature-3) are warranted.Fig. 1

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