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

M. Apicella, E. Giannoni, S. Fiore, K.J. Ferrari, D. Fernández-Pérez, C. Isella, C. Granchi, F. Minutolo, A. Sottile, P.M. Comoglio, E. Medico, F. Pietrantonio, M. Volante, D. Pasini, P. Chiarugi, S. Giordano, S. Corso

Research output: Contribution to journalArticlepeer-review


The tumor microenvironment shapes cancer progression. Apicella et al. now show that cancer-associated fibroblasts play an active metabolic role in adaptive cancer drug resistance to tyrosine kinase inhibitors (TKIs). Targeting the non-cell-autonomous lactate/HGF/MET-signaling axis abrogated acquired TKI resistance in cancer models. © 2018 Elsevier Inc. 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 κB-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. © 2018 Elsevier Inc.
Original languageEnglish
Pages (from-to)848
JournalCell Metabolism
Issue number6
Publication statusPublished - 2018


  • CAFs
  • EGFR
  • lactate
  • LDH
  • MCT1/4
  • resistance
  • targeted therapy
  • tumor metabolism
  • tumor microenvironment


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