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

Maria Apicella, Elisa Giannoni, Stephany Fiore, Karin Johanna Ferrari, Daniel Fernández-Pérez, Claudio Isella, Carlotta Granchi, Filippo Minutolo, Antonino Sottile, Paolo Maria Comoglio, Enzo Medico, Filippo Pietrantonio, Marco Volante, Diego Pasini, Paola Chiarugi, Silvia Giordano, Simona Corso

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)848-865.e6
JournalCell Metabolism
Volume28
Issue number6
DOIs
Publication statusPublished - Dec 4 2018

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Protein-Tyrosine Kinases
Lactic Acid
Tumor Microenvironment
Hepatocyte Growth Factor
Neoplasms
Receptor Protein-Tyrosine Kinases
Glycolysis
Drug Resistance
Lung Neoplasms
Therapeutics
Pharmacology
Pharmaceutical Preparations
Cancer-Associated Fibroblasts

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Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies. / Apicella, Maria; Giannoni, Elisa; Fiore, Stephany; Ferrari, Karin Johanna; Fernández-Pérez, Daniel; Isella, Claudio; Granchi, Carlotta; Minutolo, Filippo; Sottile, Antonino; Comoglio, Paolo Maria; Medico, Enzo; Pietrantonio, Filippo; Volante, Marco; Pasini, Diego; Chiarugi, Paola; Giordano, Silvia; Corso, Simona.

In: Cell Metabolism, Vol. 28, No. 6, 04.12.2018, p. 848-865.e6.

Research output: Contribution to journalArticle

Apicella, Maria ; Giannoni, Elisa ; Fiore, Stephany ; Ferrari, Karin Johanna ; Fernández-Pérez, Daniel ; Isella, Claudio ; Granchi, Carlotta ; Minutolo, Filippo ; Sottile, Antonino ; Comoglio, Paolo Maria ; Medico, Enzo ; Pietrantonio, Filippo ; Volante, Marco ; Pasini, Diego ; Chiarugi, Paola ; Giordano, Silvia ; Corso, Simona. / Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies. In: Cell Metabolism. 2018 ; Vol. 28, No. 6. pp. 848-865.e6.
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AU - Apicella, Maria

AU - Giannoni, Elisa

AU - Fiore, Stephany

AU - Ferrari, Karin Johanna

AU - Fernández-Pérez, Daniel

AU - Isella, Claudio

AU - Granchi, Carlotta

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AU - Volante, Marco

AU - Pasini, Diego

AU - Chiarugi, Paola

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AU - Corso, Simona

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