GSE115172
Increased lactate secretion by cancer cells sustains non-cell-autonomous adaptive resistance to MET and EGFR targeted therapies.
Microenvironment is known to influence cancer drug response and sustain resistance to therapies targeting receptor-tyrosine kinases. However if and how tumor microenvironment can be altered during treatment, contributing to resistance onset is not known. Here we show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift towards increased glycolysis and lactate production. We identified secreted lactate as the key molecule able to instruct Cancer Associated Fibroblasts (CAFs) to produce Hepatocyte Growth Factor (HGF) in a NF-KB dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional targeting or pharmacological inhibition of lactate dehydrogenase prevented and overcame in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This non-cell-autonomous, adaptive resistance mechanism was observed in NSCLC patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance Overall design: RNA-seq analysis of 2 different samples, each one with 2 biological replicates (4 sequencing runs in total).