期刊
CELL METABOLISM
卷 28, 期 6, 页码 848-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2018.08.006
关键词
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资金
- University of Torino, Fondo Ricerca Locale 2013
- PROGETTO ATENEO/Compagnia San Paolo 2016, University of Torino
- Italian Association for Cancer Research (AIRC) [20210]
- Fondazione Piemontese per la Ricerca sul Cancro (ONLUS) 5 X 1000 Fondi Ministero della Salute 2013
- Fondazione Piemontese per la Ricerca sul Cancro (ONLUS) 5 X 1000 Fondi Ministero della Salute 2014
- Fondazione Veronesi Research Fellowship
The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if and how the tumor microenvironment can be altered during treatment, contributing to resistance onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift toward increased glycolysis and lactate production. We identified secreted lactate as the key molecule instructing cancer-associated fibroblasts to produce hepatocyte growth factor (HGF) in a nuclear factor KB-dependent manner. Increased HGF, activating MET-dependent signaling in cancer cells, sustained resistance to TKIs. Functional or pharmacological targeting of molecules involved in the lactate axis abrogated in vivo resistance, demonstrating the crucial role of this metabolite in the adaptive process. This adaptive resistance mechanism was observed in lung cancer patients progressed on EGFR TKIs, demonstrating the clinical relevance of our findings and opening novel scenarios in the challenge to drug resistance.
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