Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor

Authors

Diego D. Manavella, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Blair McNamara, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Justin Harold, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Stefania Bellone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Tobias Max Hartwich, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Yang Yang-Hartwich, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Levent Mutlu, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Margherita Zipponi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Cem Demirkiran, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Miguel Skyler Verzosa, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Gary Altwerger, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Elena Ratner, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Gloria S. Huang, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Mitchell Clark, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Vaagn Andikyan, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Masoud Azodi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Peter E. Schwartz, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Peter R. Dottino, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Jungmin Choi, Department of Biomedical Sciences, Korea University College of Medicine, 02841 Seoul, Republic of Korea.
Ludmil B. Alexandrov, Department of Cellular and Molecular Medicine University of California San Diego, La Jolla, USA.
Natalia Buza, Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Pei Hui, Department of Pathology, Yale University School of Medicine, CT 06520, USA.
Alessandro D. Santin, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA. Electronic address: alessandro.santin@yale.edu.

Document Type

Article

Publication Title

Gynecologic oncology

Abstract

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 IC ± 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.

First Page

98

Last Page

105

DOI

10.1016/j.ygyno.2022.12.003

Publication Date

2-1-2023

Recommended Citation

Manavella, Diego D.; McNamara, Blair; Harold, Justin; Bellone, Stefania; Hartwich, Tobias Max; Yang-Hartwich, Yang; Mutlu, Levent; Zipponi, Margherita; Demirkiran, Cem; Verzosa, Miguel Skyler; Altwerger, Gary; Ratner, Elena; Huang, Gloria S.; Clark, Mitchell; Andikyan, Vaagn; Azodi, Masoud; Schwartz, Peter E.; Dottino, Peter R.; Choi, Jungmin; Alexandrov, Ludmil B.; Buza, Natalia; Hui, Pei; and Santin, Alessandro D., "Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor" (2023). Obstetrics and Gynecology. 152.
https://scholar.bridgeporthospital.org/obgyn/152

Identifier

36525930 (pubmed); NIHMS1858349 (mid); PMC9925406 (pmc); 10.1016/j.ygyno.2022.12.003 (doi); S0090-8258(22)01982-5 (pii)