There is limited knowledge about the metabolic reprogramming induced by cancer
therapies, and how this contributes to therapeutic resistance. Here we show that
although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and
restrained tumor growth, these signaling and metabolic restrictions triggered autophagy,
which supplied the metabolites required for the maintenance of mitochondrial respiration
and redox homeostasis. Specifically, we found that survival of cancer cells was critically
dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty
acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this,
we observed significantly increased lipid droplets, with subsequent mobilization to
mitochondria. These changes were abrogated in cells deficient for the essential
autophagy gene, ATG5. Accordingly, inhibition of PLA2 significantly decreased lipid
droplets, decreased oxidative phosphorylation and increased apoptosis. Together, these
results describe how treatment-induced autophagy provides nutrients for cancer cell
survival and identifies novel co-treatment strategies to override this survival advantage
