Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies.

摘要: Summary The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if how the tumor can be altered during treatment, contributing onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cells displayed a metabolic shift toward increased glycolysis lactate production. identified secreted as key molecule instructing cancer-associated fibroblasts produce hepatocyte growth factor (HGF) in nuclear κB-dependent manner. Increased HGF, activating MET-dependent signaling cells, sustained TKIs. Functional pharmacological of molecules involved axis abrogated in vivo resistance, demonstrating crucial role this metabolite adaptive process. This mechanism was observed lung patients progressed on EGFR TKIs, clinical relevance our findings opening novel scenarios challenge resistance.