Efficacy of ATR Kinase Inhibitor Elimusertib Monotherapy or Combination in Tumors with DNA Damage Response Pathway and Other Genomic Alterations

Authors

Kaushik Varadarajan
Christian X Cruz Pico
Kurt W Evans
Maria Gabriela Raso
Yasmeen Qamar Rizvi
Xiaofeng Zheng
Dhruv Chachad
Timothy P DiPeri
Bailiang Wang
Stephen M Scott
Ming Zhao
Argun Akcakanat
Antje M Wengner
Timothy A Yap
Funda Meric-Bernstam

Publication Date

9-2-2025

Journal

Molecular Cancer Therapeutics

DOI

10.1158/1535-7163.MCT-24-0884

PMID

40300249

PMCID

PMC12402799

PubMedCentral® Posted Date

5-14-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia-mutated (ATM) kinase as a modulator of DNA damage response (DDR). We assessed the antitumor effects of the ATR inhibitor elimusertib (BAY-1895344) in patient-derived xenograft (PDX) models with DDR alterations. Antitumor activity was assessed by change in tumor volume (TV) from baseline. Responses were categorized as follows: partial response (PR), ≥30% decrease in TV; ≥20% increase in TV, progressive disease; and non-PR/progressive disease, stable disease (SD). Event-free survival was defined as time for tumor doubling (EFS-2). Of 21 PDX models tested, 11 had significant prolongation of EFS-2 with elimusertib monotherapy. Four models had a PR and four had SD. PR/SD was observed in two of five models with ATM loss on IHC and in models with a variety of alterations in DDR genes, including BRCA1/2 and ATM. Elimusertib prolonged EFS-2 in three of five models with known PARP inhibitor resistance. Pharmacodynamic studies conducted in four PDX models showed an increase in DNA damage markers. PI3K/mTOR pathway signaling increased in two of four models. The combination of the PI3K inhibitor copanlisib with elimusertib enhanced EFS-2 compared with monotherapy in three of 11 models tested. The combination of elimusertib with the PARP inhibitor niraparib enhanced antitumor activity compared with single agents in PARP-resistant PDX models. Our study shows that ATR inhibition has antitumor activity, including in models with both intrinsic and acquired PARP inhibitor resistance. Further work is needed to better refine patient selection for ATR-based therapies.

Keywords

Humans, Animals, DNA Damage, Mice, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Ataxia Telangiectasia Mutated Proteins, Female, Neoplasms, Cell Line, Tumor

Published Open-Access

yes

Recommended Citation

Varadarajan, Kaushik; Cruz Pico, Christian X; Evans, Kurt W; et al., "Efficacy of ATR Kinase Inhibitor Elimusertib Monotherapy or Combination in Tumors with DNA Damage Response Pathway and Other Genomic Alterations" (2025). Faculty, Staff and Student Publications. 4829.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4829