Abstract 6180: Antitumor activity of the ATR inhibitor Elimusertib in patient-derived xenograft models with DNA damage response pathway alterations
Authors: Varadarajan Kaushik , Pico Christian X. , Evans Kurt , Raso Maria G. , Rizvi Yasmeen , Zheng Xiaofeng , Diperi Timothy P. , Wang Bailiang , Scott Stephen , Zhao Ming , Akcakanat Argun , Wengner Antje M. , Yap Timothy A. , Meric-Bernstam Funda 
Published: April 2023

Abstract
Introduction: The ataxia telangiectasia and RAD3-related (ATR) kinase is a key component of the DNA damage response (DDR) and functions in conjunction with ataxia telangiectasia mutated (ATM). ATM loss or functional deficiency may enhance reliance on ATR signaling. Preclinical and clinical studies have pointed to a potential synthetic lethality of ATR inhibition and ATM loss. In this study, we sought to further elaborate potential candidates for ATR inhibition by testing the anti-tumor effect of elimusertib (BAY 1895344) in patient-derived tumor xenograft (PDX) models with DDR alterations including ATM loss.
Methods: Patient derived xenograft (PDX) models were implanted into athymic nu/nu mice. Once tumors reached an appropriate size of approximately 200-400mm3 treatments were started. Mice were randomized (N= 3-8) to different treatment arms for assessment of anti-tumor activity of elimusertib as monotherapy and in combination therapy with copanlisib. Monotherapy treatment was performed with 20 mg/kg and 40 mg/kg doses, applied twice daily for 3 days with 4 days treatment break (BID 3 days on/4 days off). Efficacy read-out was either Event-Free Survival (EFS-2), defined as time for doubling of tumor volume relative to baseline, or response based on RECIST criteria:(partial response [PR]= &gt;30% decrease, stable disease [SD]= between 20% increase and 30% decrease, and progressive disease [PD]= &gt;20% increase). For assessment of pharmacodynamic effects, tumors were harvested 10 days after treatment start and analyzed by immunohistochemistry (IHC) and RPPA (Reverse Phase Proteomics Array).
Results: Elimusertib was tested in 21 PDX models with various DDR alterations. Of those 11 showed a statistically significant prolongation of event free survival compared to control. In 4 PDX models elimusertib reached a partial response (PR), and another 4 models showed stable disease (SD). Amongst the 5 models with ATM protein Ioss (IHC), one was PR and another one SD. In 3 of 5 PARP inhibitor resistant there was statistically significant prolongation of EFS upon elimusertib treatment vs control. We found an increase in DNA damage in tumors, as indicated by increased level of ƳH2AX (on IHC and RPPA). We also detected an increase in PI3K/mTOR pathway signaling as determined by p-MTOR and pS6 (RPPA) in 2 of 4 models (PR and PD model) with different sensitivity to ATRi and PARPi alone. We tested the combination of elimusertib with the PI3K inhibitor copanlisib achieved a statistically significant increase of EFS compared to monotherapy in 3 of 11 models tested.
Conclusion ATR inhibition shows potent monotherapy activity in selected PDX models that harbor DDR defects, including models with intrinsic and acquired PARPi resistance. Further work is needed to identify markers predicting sensitivity or resistance that providing rationale for synergistic combination therapies.
Citation Format: Kaushik Varadarajan, Christian X. Pico, Kurt Evans, Maria G. Raso, Yasmeen Rizvi, Xiaofeng Zheng, Timothy P. Diperi, Bailiang Wang, Stephen Scott, Ming Zhao, Argun Akcakanat, Antje M. Wengner, Timothy A. Yap, Funda Meric-Bernstam. Antitumor activity of the ATR inhibitor Elimusertib in patient-derived xenograft models with DNA damage response pathway alterations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6180.