Ovarian and uterine carcinosarcoma cell lines show preclinical sensitivity to BAY 1895344, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor (011)

Diego Manavella,Justin Harold,Stefania Bellone,Tobias Hartwich,Levent Mutlu,Joan Tymon-Rosario,Eric Siegel,Gary Altwerger,Gulden Menderes,Elena Ratner,Gloria Huang,Mitchell Clark,Vaagn Andikyan,Masoud Azodi,Peter Schwartz,Ludmil Alexandrov,Alessandro Santin

doi:10.1016/s0090-8258(22)01229-x

Abstract

Objectives: Carcinosarcoma (CS) of the ovary (OCS) and uterus (UCS) are highly aggressive malignancies, poorly responsive to currently available adjuvant treatment. Ataxia-telangiectasia and Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair (DDR). Homologous recombination (HR) deficiency has been demonstrated in 60% of OCS and 17% of UCS. BAY 1895344 is a selective ATR kinase inhibitor that has proved strong monotherapy efficacy in models that carry DDR deficiencies, such as HRD. This study aimed to test in vitro and in vivo preclinical activity of BAY 1895344 in both HR deficient (HRD) and proficient (HRP) OCS and UCS cell lines and xenograft models. Methods: Sensitivity to BAY 1895344 was evaluated in vitro against nine fully whole-exome sequenced (WES) primary CS cell lines according to HR status. BAY 1895344 antitumor activity was tested in vivo against an HRD CS xenograft model. Results: Of the nine primary fully WES CS cell lines, three were HRD (2 OCS vs 1 UCS) and six HRP (5 UCS vs 1 OCS). In vitro sensitivity to BAY 1895344 was observed in seven out of nine CS cell lines (Figure A). While a trend was observed for higher sensitivity (i.e., lower IC50) in HRD tumors (mean IC50 ± SEM HRD: 64.44 nM ± 15.18 vs HRP: 147.2 nM ± 68.7); however, this difference was not statistically significant (p=0.4244) (Figure A). In vivo, BAY 1895344 showed significant tumor growth inhibition in HRD CS xenografts (p<0.0001) (Figure B) and increased overall animal survival (p<0.0001) (Figure C). No significant toxicity was observed when compared to vehicle controls. Conclusions: Most primary OCS and UCS cell lines with and without HRD signature (Signature-3) by WES are sensitive in vitro to BAY 1895344. Furthermore, in vivo, primary HRD OCS xenografts are responsive to the drug. While further research will be necessary to determine the mechanisms underlying ATR kinase inhibition sensitivity in HRP CS, clinical studies with BAY 1895344 in CS patients with an HRD signature are warranted.Fig. 1

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