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Glucose is an essential fuel for cell survival and its availability limits aberrant cellular proliferation. We have hypothesized that specific cancer mutations regulate metabolic response(s) to glucose deprivation (GD). By means of somatic knock-in cellular models, we have analyzed the response to glucose deprivation in cells carrying the frequent   delE746-A750 EGFR ,   G13D KRAS  or   E545K PIK3CA  cancer alleles. We demonstrate that, in mammary epithelial cells, glucose has an essential antioxidant function and that these cells are very sensitive to GD. Conversely, isogenic cells carrying the   delE746-A750 EGFR  or the   E545K PIK3CA , but not the   G13D KRAS  allele, display high tolerance to GD by stimulating the expression of anti-oxidant genes ( MnSOD  and  catalase ). This adaptive transcriptional response is mediated by the activation of WNT/β-catenin and FOXO4 signalling. Our data highlights a new functional synergism between oncogenic EGFR and PIK3CA with WNT/β-catenin conferring high tolerance to oxidative stress generated by nutrient deprivation.

Activation of β-Catenin by Oncogenic PIK3CA and EGFR Promotes Resistance to Glucose Deprivation by Inducing a Strong Antioxidant Response