Metformin selectively inhibits metastatic colorectal cancer with the KRAS mutation by intracellular accumulation through silencing MATE1
Menée à l'aide de lignées cellulaires, d'échantillons tumoraux issus de patients atteints d'un cancer colorectal métastatique et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel la metformine, en raison de la suppression de l'expression de la protéine MATE1 par les oncoprotéines KRAS mutées, peut s'accumuler dans les cellules cancéreuses avec mutation du gène KRAS et inhiber leur développement
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.Metastatic colorectal cancer (mCRC) patients have poor overall survival despite using irinotecan- or oxaliplatin-based chemotherapy combined with anti-EGFR (epidermal growth factor receptor) drugs, especially those with the oncogene mutation of KRAS. Metformin has been reported as a potentially novel antitumor agent in many experiments, but its therapeutic activity is discrepant and controversial so far. Inspiringly, 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. In contrast, metformin could not improve the survival of mCRC patients with wild-type KRAS. Interestingly, metformin is preferentially accumulated in KRAS-mutation mCRC cells, but not wild-type ones, in both primary cell cultures and patient-derived xenografts, which is in agreement with its tremendous effect in KRAS-mutation mCRC. Mechanistically, the mutated KRAS oncoprotein hypermethylates and silences the expression of multidrug and toxic compound extrusion 1 (MATE1), a specific pump that expels metformin from the tumor cells by up-regulating DNA methyltransferase 1 (DNMT1). Our findings provide evidence that KRAS-mutation mCRC patients benefit from metformin treatment and targeting MATE1 may provide a strategy to improve the anticancer response of metformin.