DIFFERENTIAL EFFECTS OF FASTING AND PHARMACOLOGICAL INTERVENTIONS ON CANCER AND CANCER STEM CELLS

Approximately 10-15% of breast carcinomas are classified as triple receptor-negative breast cancer (TNBC) subtype because of the lack of expression of hormone receptors. Despite the advent of new therapeutic strategies, tumor relapses remain the major challenge in TNBC management. Several studies show that treatment failure and cancer recurrence are primarily due to drug resistance acquisition and self-renewal that are specific properties of cancer stem cells (CSCs). Here I show that a fasting mimicking diet (FMD) reduces the percentage of the staminal population in mouse models of TNBC, increasing cancer free survival, and that the mechanism through which it affects CSCs is glucose dependent and mediated, at least in part, by the down-regulation of the protein kinase A (PKA) pathway. Moreover, the use of RNA-seq analysis on TNBC tumor masses, after FMD, allowed the identification of druggable escape pathways, in particular PI3K/AKT, mTOR and CCND/CDK4-6 axis, activated selectively by differentiated cells. My results show that addition of FMD to inhibitors of these pathways promotes TNBC regression, leading to complete tumor shrinkage. Notably, FMD protects also from hyperglycemia induced by PI3K pathway inhibitors, preventing side effects associated with it. Taken together, these data indicate that FMD has wide but differential effects reaching normal as well as differentiated cancer cells and CSCs, thus representing a promising strategy for the treatment of TNBC, which can be hopefully translated into the clinic.