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Research advances in the treatment of KRAS mutant colorectal cancer from Prof. Guoquan Gao’s group at Zhongshan School of Medicine

Last updated :2020-06-02

Source: Zhongshan School of Medicine
Written by: Zhongshan School of Medicine
Edited by: Tan Rongyu, Wang Dongmei

Colorectal cancer (CRC) is the 3rd most common cancer and the leading cause of cancer death worldwide, and the mutation rate of KRAS gene in colorectal cancer patients is as high as 30%-50%. KRAS gene mutation is a key factor leading to tumor metastasis and recurrence. A large number of clinical studies have shown that such patients fail to benefit from anti-EGFR targeted therapy, leading to a rapid increase in the cancer-related mortality of colorectal cancer. Current therapeutic strategies for CRC with KRAS mutations focus on the inhibition of KRAS activation or the activation of MEK/ERK, the downstream proliferation-promoting signaling pathway of KRAS. However, both have failed in phase II clinical trials.Therefore, it has become imperative to look for new drugs targeting KRAS-mutation cancer.

Recently, the team of Professor Guoquan Gao from Zhongshan School of Medicine at Sun Yat-sen University has made new progress in the research of metformin in the treatment of KRAS mutant colorectal cancer. The study has been published in Proceedings of the National Academy of Sciences of the United States of America (PNAS), entitled “Metformin selectively inhibits metastatic colorectal cancer with KRAS mutation by intracellular accumulation through silencing MATE1”.

A schematic of the regulation of metform concentration in KRAS- wildtype and KRAS-mutation CRC cells
 
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 team found that the median survival time for KRAS mutation mCRC patients with diabetes on metformin is 37.8 month 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 patients. 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 upregulating DNA methyltransferase 1 (DNMT1). The present 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.The team is conducting prospective clinical trials at Sun Yat-sen University Cancer Center, which will provide more direct evidence of metformin use.

Jinye Xie (Ph.D. student), Liangping Xia (Professor, Sun Yat-sen University Cancer Center), Wei Xiang (Ph.D. student), and Wenzhuo He (Ph.D. student, Sun Yat-sen University Cancer Center) are the first authors. Professor Gao Guoquan, Associate Professor Ti Zhou and Professor Xia Yang are co-corresponding authors. This research was supported by the National Key R&D Program of China and National Natural Science Foundation of China.

Link to the paper: https://www.pnas.org/content/early/2020/05/21/1918845117