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

Abstract

Colorectal cancer (CRC) driven by <i>PTEN</i> 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 <i>PTEN</i>^-/- CRC cells. MDM2 inhibition in turn activated p53 in CRC, particularly in <i>PTEN</i>^-/- CRC cells. The synthetic lethal effect of MDM2 inhibitor was largely dependent on p53, because p53 silenced cells or cells lacking p53 failed to exhibit synthetic lethality in PTEN-deficient cells. We further showed that MDM2 inhibition led to the p53-dependent reversal of Bcl2-Bax ratio, which contributed to mitochondria-mediated apoptotic cell death in PTEN-deficient CRC. This study suggests that pharmacological targeting of MDM2 could be a potential therapeutic strategy for PTEN-deficient CRC.