METFORMIN AND GLUCOSE STARVATION ATTENUATE THE DNA-DAMAGE RESPONSE THROUGH THE ACTIVATION OF PROTEIN PHOSPHATASE 2A

The DNA-Damage Response (DDR) mediates DNA-damage sensing and repair. Protein Phosphatase 2A (PP2A) is a major phosphatase in eukaryotes and plays a critical role in countless cellular processes. Among them, PP2A has been shown to modulate the DDR, although many aspects of this regulation remain to be better characterized. PP2A integrates metabolic sensing with the DDR in yeast. Through a pharmacological and genetic approach, our group found that the combination of metformin (the most commonly used drug for type 2 diabetes) with glucose starvation increased PP2A activity. In Triple Negative Breast Cancer (TNBC) cell lines and patient-derived tumors, metformin and glucose starvation enhanced the efficacy of low-dose, DNA-damaging chemotherapy. We demonstrated that PP2A, over-activated by metformin and glucose starvation, attenuated the DDR triggered by chemotherapy, thus preventing the cell cycle arrest necessary for DNA repair and increasing genomic fragmentation, which finally led to cell death. We showed that metformin and glucose starvation increased PP2A recruitment on the chromatin; this could stabilize PP2A catalytic subunit and increase its phosphatase activity. In mouse models of TNBC, metformin and cycles of intermittent fasting (which lowered blood glucose) increased the efficacy of low-dose chemotherapy and induced tumor regression. Targeting the DDR is considered an attractive therapeutic opportunity, based on the intrinsic genomic instability of tumor cells. Here we provide a metabolic strategy to mitigate the DDR at multiple levels, which is safe, tolerable and immediate.