ATR inhibition reverses the resistance of homologous recombination deficient MGMT^low/MMR^proficient cancer cells to temozolomide.

ABSTRACT: The therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all MGMT^low/-ve/MMR^proficient patients benefit from TMZ treatment, indicating a need for additional patient selection criteria. We explored the role of ATR in mediating TMZ resistance and whether ATR inhibitors (ATRi) could reverse this resistance in multiple cancer lines. We observed that only 31% of MGMT^low/-ve/MMR^proficient patient-derived and established cancer lines are sensitive to TMZ at clinically relevant concentrations. TMZ treatment resulted in DNA damage signaling in both sensitive and resistant lines, but prolonged G₂/M arrest

SUBMITTER: El Touny LH 

PROVIDER: S-EPMC8522839 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature