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

Diego D. Manavella, Blair McNamara, Justin Harold, Stefania Bellone, Tobias Max Philipp Hartwich, Yang Yang-Hartwich, Levent Mutlu, Margherita Zipponi, Cem Demirkiran, Miguel Skyler Verzosa, Gary Altwerger, Elena Ratner, Gloria S. Huang, Mitchell Clark, Vaagn Andikyan, Masoud Azodi, Peter E. Schwartz, Peter R. Dottino, Jungmin Choi, Ludmil B. AlexandrovNatalia Buza, Pei Hui, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)98-105
Number of pages8
JournalGynecologic Oncology
Volume169
DOIs
Publication statusPublished - 2023 Feb

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • ATR inhibitors
  • ATRX
  • BAY1895344
  • Carcinosarcomas
  • Elimusertib

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynaecology

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