TY - JOUR
T1 - 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
AU - Tymon-Rosario, Joan R.
AU - Manara, Paola
AU - Manavella, Diego D.
AU - Bellone, Stefania
AU - Hartwich, Tobias Max Philipp
AU - Harold, Justin
AU - Yang-Hartwich, Yang
AU - Zipponi, Margherita
AU - Choi, Jungmin
AU - Jeong, Kyungjo
AU - Mutlu, Levent
AU - Yang, Kevin
AU - Altwerger, Gary
AU - Menderes, Gulden
AU - Ratner, Elena
AU - Huang, Gloria S.
AU - Clark, Mitchell
AU - Andikyan, Vaagn
AU - Azodi, Masoud
AU - Schwartz, Peter E.
AU - Alexandrov, Ludmil B.
AU - Santin, Alessandro D.
N1 - Funding Information:
This work was supported in part by grants from NIH U01 CA176067-01A1 , the Deborah Bunn Alley Foundation , the Domenic Cicchetti and the Discovery to Cure Foundation and the Guido Berlucchi Foundation to A.D.S., and Gilead Sciences Inc ., Foster City, CA. This investigation was also supported by NIH Research Grant CA-16359 from NCI and Standup-to-cancer (SU2C) convergence grant 2.0 to Alessandro Santin.
Publisher Copyright:
© 2022
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - Carcinosarcoma
KW - Homologous-recombination-deficiency (HRD)
KW - Poly(ADP-ribose)-polymerase inhibitors (PARPi)
KW - Whole-exome-sequencing (WES)
UR - http://www.scopus.com/inward/record.url?scp=85130496124&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2022.05.005
DO - 10.1016/j.ygyno.2022.05.005
M3 - Article
C2 - 35599167
AN - SCOPUS:85130496124
SN - 0090-8258
VL - 166
SP - 117
EP - 125
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 1
ER -