The antidiabetic drug metformin appears to lower cancer risk in diabetic patients and has shown antitumor activity in preclinical studies. Suppression of mTOR signaling via AMP kinase (AMPK)-dependent TOR complex 1 (TORC1) inhibition is one of the proposed mechanisms by which metformin appears to suppress cancer cell growth.
In recent studies, Martin and colleagues from the University of Manchester in the UK showed that BRAF-mutant (but not NRAS-mutant) melanoma cells were resistant to metformin on the basis of constitutive TORC1 activation mediated by RSK (ribosomal S6 kinase) that occurred despite AMPK activation. Metformin accelerated the angiogenesis and growth of BRAF-mutant melanoma xenografts in association with upregulation of vascular endothelial growth factor A (VEGF-A).
Upregulation of VEGF-A was shown to result from increased ERK activity caused by AMPK-mediated degradation of the dual-specificity protein phosphatase DUSP6. However, a synergistic effect in reducing growth of BRAF-mutant xenografts was found when metformin was combined with a small-molecule VEGF receptor inhibitor (axitinib [Inlyta]), a neutralizing VEGF antibody (bevacizumab [Avastin]), or stable expression of a VEGF-A short hairpin RNA.
These findings have potential implications for both the treatment of diabetic patients with melanoma and treatment of BRAF-mutant cancers. As stated by the investigators, “Metformin inhibits the growth of most tumor cells, but BRAF-mutant melanoma cells are resistant to metformin in vitro, and metformin accelerates their growth in vivo. Unexpectedly, VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these patients.” ■
Martin MJ, et al: Cancer Discov 2:344-355, 2012.