MDM2 inhibition is synthetic lethal with PTEN loss in colorectal cancer cells via the p53-dependent mechanism.

ABSTRACT: Colorectal cancer (CRC) driven by PTEN deficiency exhibits high risk of metastasis, advancement of tumor stages and chemotherapy resistance, where no effective therapy has been developed. In this study, we performed a synthetic lethal drug screening in CRC and found that PTEN-deficient CRC cells are highly vulnerable to MDM2 inhibition. MDM2 inhibitor treatment or its silencing selectively inhibited the growth of PTEN-deficient CRC in vitro and in mice models. Mechanistically, PTEN loss increased the level of active AKT and subsequently increased MDM2 phosphorylation, thereby limiting the p53 functions in PTEN^-/- CRC cells. MDM2 inhibition in turn activated p53 in CRC, particularly in PTEN^-/- CRC cells. The synthetic lethal effect of MDM2 inhibito

SUBMITTER: Ren G 

PROVIDER: S-EPMC10367566 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature