Predictors of Cancer Cell Response to Metformin
Abstract
There is great interest in transitioning the antidiabetic drug metformin for use in cancer, with evidence suggesting it can improve outcome following radiotherapy (RT). Its benefit may arise from inhibiting cancer cell proliferation, abrogating tumour hypoxia through respiratory inhibition, or directly radiosensitizing cancer cells. With metformin entering clinical trials, it is crucial to identify relevant biomarkers for patient benefit. AMPK and p53 were previously identified to facilitate metformin's radiosensitization, while OCT and MATE transporters mediate its intracellular concentration: we thus investigated these as contributors to metformin's radiosensitizing, anti-proliferative, or respiratory-inhibitory effects. We found that loss of AMPK or p53 exacerbated sensitivity to metformin's inhibition of proliferation, while OCT expression was sufficient to confer response to metformin's respiratory inhibition. Together, loss of AMPK and p53 signaling, and OCT expression, represent putative biomarkers of response to inhibition of proliferation and respiration, respectively, and may be further explored in a clinical setting.
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