학술논문
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.
Document Type
Article
Author
Tymon-Rosario, Joan R.; Manara, Paola; Manavella, Diego D.; Bellone, Stefania; Hartwich, Tobias Max Philipp; Harold, Justin; Yang-Hartwich, Yang; Zipponi, Margherita; Choi, Jungmin; Jeong, Kyungjo; Mutlu, Levent; Yang, Kevin; Altwerger, Gary; Menderes, Gulden; Ratner, Elena; Huang, Gloria S.; Clark, Mitchell; Andikyan, Vaagn; Azodi, Masoud; Schwartz, Peter E.
Source
Subject
*POLY ADP ribose
*ADENOSINE diphosphate
*OLAPARIB
*RIBOSE
*POLY(ADP-ribose) polymerase
*CARCINOSARCOMAS
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Language
ISSN
0090-8258
Abstract
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. 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. 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 IC 50 ± 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). 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. • 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 FROM AUTHOR]