Metformin selectively inhibits metastatic colorectal cancer with the <i>KRAS</i> mutation by intracellular accumulation through silencing MATE1

Abstract

Significance CRC patients with KRAS mutations are confronted with limited targeted therapeutic options. In this study, we have shown that the median survival time for KRAS -mutation mCRC patients with diabetes on metformin is 37.8 mo longer than those treated with other hypoglycemic drugs in combination with standard systemic therapy. Metformin is preferentially accumulated in KRAS -mutation CRC cells in both primary cell cultures and patient-derived xenografts. The promising therapeutic activity of metformin has a negative correlation with MATE1 expression, which is proven to eliminate metformin from CRC cells. These findings indicate that KRAS -mutation mCRC patients could benefit from metformin treatment, and somatic KRAS status or MATE1 expression should be recommended to predict the therapeutic response of metformin in CRC.