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 1, Blair McNamara 1, Justin Harold 1, Stefania Bellone 1, Tobias Max Philipp Hartwich 1, Yang Yang-Hartwich 1, Levent Mutlu 1, Margherita Zipponi 1, Cem Demirkiran 1, Miguel Skyler Verzosa 1, Gary Altwerger 1, Elena Ratner 1, Gloria S Huang 1, Mitchell Clark 1, Vaagn Andikyan 1, Masoud Azodi 1, Peter E Schwartz 1, Peter R Dottino 1, Jungmin Choi 2, Ludmil B Alexandrov 3, Natalia Buza 4, Pei Hui 4, Alessandro D Santin 5

Background: Carcinosarcoma from 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) continues to be shown 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 as well as in vivo against HRD CS xenografts. Western blots were performed to find out baseline ATR and p-ATR protein expression in CS, and ATR path downstream effectors and apoptosis markers in CS HRD cell lines after Elimusertib treatment.

Results: From the 9 CS cell lines, 3 harbored HRD and 6 homologous recombination proficient (HRP) features. The majority of CS (i.e., 7/9 = 85%) were discovered to be responsive to Elimusertib in vitro. One of the 5 primary CS cell lines having a high-grade pure serous epithelial component, HRD cell lines were more responsive to elimusertib than HRP tumors (mean IC50 ?¨¤ SEM HRD CS = 61.3 nM ?¨¤15.2 versus HRP = 361.6 nM ?¨¤24.4 (p = .01)). Baseline ATR and p-ATR protein expression was greater in HRD CS cell lines. Elimusertib demonstrated 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.