TY - JOUR
T1 - Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor
AU - Manavella, Diego D.
AU - McNamara, Blair
AU - Harold, Justin
AU - Bellone, Stefania
AU - Hartwich, Tobias Max Philipp
AU - Yang-Hartwich, Yang
AU - Mutlu, Levent
AU - Zipponi, Margherita
AU - Demirkiran, Cem
AU - Verzosa, Miguel Skyler
AU - Altwerger, Gary
AU - Ratner, Elena
AU - Huang, Gloria S.
AU - Clark, Mitchell
AU - Andikyan, Vaagn
AU - Azodi, Masoud
AU - Schwartz, Peter E.
AU - Dottino, Peter R.
AU - Choi, Jungmin
AU - Alexandrov, Ludmil B.
AU - Buza, Natalia
AU - Hui, Pei
AU - Santin, Alessandro D.
N1 - Funding Information:
This work was supported in part by grants from NIH U01 CA176067-01A1, the Deborah Bunn Alley, the Domenic Cicchetti, the Discovery to Cure, and the Guido Berlucchi Foundations to AS. This investigation was also supported by NIH Research Grant CA-16359 from NCI and Standup-to-cancer (SU2C) convergence grant 2.0 to AS.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2023/2
Y1 - 2023/2
N2 - Background: Carcinosarcoma of the ovary (OCS) and uterus (UCS) are rare highly aggressive malignancies. Ataxia-telangiectasia-and-Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair. Homologous recombination deficiency (HRD) has been demonstrated in >30% of OCS/UCS. We investigated the preclinical activity of elimusertib, a selective ATR kinase inhibitor, against carcinosarcoma (CS) cell lines and xenografts. Methods: Sensitivity to elimusertib was evaluated in vitro against nine whole exome-sequenced (WES) primary CS cell lines and in vivo against HRD CS xenografts. Western blots were performed to determine baseline ATR and p-ATR protein expression in CS, and ATR pathway downstream effectors and apoptosis markers in CS HRD cell lines after Elimusertib treatment. Results: Out of the 9 CS cell lines, 3 harbored HRD and 6 homologous recombination proficient (HRP) features. Most of CS (i.e., 7/9 = 85%) were found to be sensitive to Elimusertib in vitro. Among the 5 primary CS cell lines with a high-grade pure serous epithelial component, HRD cell lines were more sensitive to elimusertib than HRP tumors (mean IC50 ± SEM HRD CS = 61.3 nM ±15.2 vs HRP = 361.6 nM ±24.4 (p = 0.01)). Baseline ATR and p-ATR protein expression was higher in HRD CS cell lines. Elimusertib showed tumor growth inhibition in HRD CS xenografts (p < 0.0001) and increased overall animal survival (p < 0.0001). Western blot demonstrated dose-dependent inhibition of ATR, p-ATR and its downstream effector p-CHK1, and a dose-dependent increase in caspase-3 expression. Conclusions: Elimusertib is preclinically active in vitro and in vivo against primary CS cell lines and xenografts, respectively. CS models harboring HRD or with pure/mixed endometrioid histology demonstrated higher sensitivity to ATR inhibition. Clinical trials with elimusertib in CS patients are warranted.
AB - Background: Carcinosarcoma of the ovary (OCS) and uterus (UCS) are rare highly aggressive malignancies. Ataxia-telangiectasia-and-Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair. Homologous recombination deficiency (HRD) has been demonstrated in >30% of OCS/UCS. We investigated the preclinical activity of elimusertib, a selective ATR kinase inhibitor, against carcinosarcoma (CS) cell lines and xenografts. Methods: Sensitivity to elimusertib was evaluated in vitro against nine whole exome-sequenced (WES) primary CS cell lines and in vivo against HRD CS xenografts. Western blots were performed to determine baseline ATR and p-ATR protein expression in CS, and ATR pathway downstream effectors and apoptosis markers in CS HRD cell lines after Elimusertib treatment. Results: Out of the 9 CS cell lines, 3 harbored HRD and 6 homologous recombination proficient (HRP) features. Most of CS (i.e., 7/9 = 85%) were found to be sensitive to Elimusertib in vitro. Among the 5 primary CS cell lines with a high-grade pure serous epithelial component, HRD cell lines were more sensitive to elimusertib than HRP tumors (mean IC50 ± SEM HRD CS = 61.3 nM ±15.2 vs HRP = 361.6 nM ±24.4 (p = 0.01)). Baseline ATR and p-ATR protein expression was higher in HRD CS cell lines. Elimusertib showed tumor growth inhibition in HRD CS xenografts (p < 0.0001) and increased overall animal survival (p < 0.0001). Western blot demonstrated dose-dependent inhibition of ATR, p-ATR and its downstream effector p-CHK1, and a dose-dependent increase in caspase-3 expression. Conclusions: Elimusertib is preclinically active in vitro and in vivo against primary CS cell lines and xenografts, respectively. CS models harboring HRD or with pure/mixed endometrioid histology demonstrated higher sensitivity to ATR inhibition. Clinical trials with elimusertib in CS patients are warranted.
KW - ATR inhibitors
KW - ATRX
KW - BAY1895344
KW - Carcinosarcomas
KW - Elimusertib
UR - http://www.scopus.com/inward/record.url?scp=85143896870&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2022.12.003
DO - 10.1016/j.ygyno.2022.12.003
M3 - Article
AN - SCOPUS:85143896870
SN - 0090-8258
VL - 169
SP - 98
EP - 105
JO - Gynecologic Oncology
JF - Gynecologic Oncology
ER -