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 - 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 -