MTORC1 and DNA-PKcs as novel molecular determinants of sensitivity to Chk1 inhibition.

ABSTRACT:

Background

Chk1 inhibitors are currently under clinical evaluation as single agents and in combination with cytotoxic chemotherapy. Understanding determinants of sensitivity and novel combinations is critical for further clinical development.

Methods

Potentiation of mTOR inhibitor cytotoxicity by the Chk1 inhibitor V158411 was determined in p53 mutant colon cancer cells. DNA damage response, expression levels of repair proteins, cell cycle effects and the contribution of alternative DSB repair pathways were further evaluated by western blotting and high content analysis.

Results

mTOR inhibitors AZD8055, RAD-001, rapamycin and BEZ235 induced synergistic cytotoxicity with the Chk1 inhibitor V158411 in p53 mutant colon cancer cells. Reduced FANCD2, RAD51 and RPA70, core

SUBMITTER: Massey AJ 

PROVIDER: S-EPMC5528927 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature