Biguanides antithetically regulate tumor properties by the dose-dependent mitochondrial reprogramming-driven c-Src pathway.

The biguanide metformin attenuates mitochondrial oxidation and is proposed as an anti-cancer therapy. However, recent clinical studies suggest increased proliferation and fatty acid β-oxidation (FAO) in a subgroup of patients with breast cancer (BC) after metformin therapy. Considering that FAO can activate Src kinase in aggressive triple-negative BC (TNBC), we postulate that low-dose biguanide-driven AMPK-ACC-FAO signaling may activate the Src pathway in TNBC. The low bioavailability of metformin in TNBC xenografts mimics metformin's in vitro low-dose effect. Pharmacological or genetic inhibition of FAO significantly enhances the anti-tumor properties of biguanides. Lower doses of biguanides induce and higher doses suppress Src signaling. Dasatinib and metformin synergistically inhibit TNBC patient-derived xenograft growth, but not in high-fat diet-fed mice. This combination also suppresses TNBC metastatic progression. A combination of biguanides with Src inhibitors provides synergy to target metastatic TNBC suffering with limited treatment options.