Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors.

ABSTRACT: O⁶-methylguanine-DNA methyltransferase (MGMT) is an enzyme that removes alkyl groups at the O⁶-position of guanine in DNA. MGMT expression is reduced or absent in many tumor types derived from a diverse range of tissues, most notably in glioma. Low MGMT expression confers significant sensitivity to DNA alkylating agents such as temozolomide, providing a natural therapeutic index over normal tissue. In this study, we sought to identify novel approaches that could maximally exploit the therapeutic index between tumor cells and normal tissues based on MGMT expression, as a means to enhance selective tumor cell killing. Temozolomide, unlike other alkylators, activated the ataxia telangiectasia and Rad3-related (ATR)-checkpoint kinase 1 (Chk1) axis in a manner that was hig

SUBMITTER: Jackson CB 

PROVIDER: S-EPMC6810597 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature