Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies
Open accessAbstract
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.
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Metabolic interactions between cancer cells and the microenvironment can promote therapy resistance.
“In some cases, metabolic interactions between cancer cells and the microenvironment promote therapy resistance.”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [111]
Lactate export by non-small-cell lung cancer cells induces neighboring fibroblasts to secrete hepatocyte growth factor, which activates c-MET on cancer cells and sustains oncogenic signaling despite EGFR inhibitors.
“Lactate export by the cancer cells induces neighboring fibroblasts to secrete hepatocyte growth factor, which activates its receptor tyrosine kinase c-MET on cancer cells. Consequently, the cancer cells sustain oncogenic signaling even in the presence of EGFR inhibitors (111).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [111]
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- Authors
- Apicella, M., Giannoni, E., Fiore, S., Ferrari, K. J., Fernández-Pérez, D., Isella, C., Granchi, C., Minutolo, F., Sottile, A., Comoglio, P. M., Medico, E., Pietrantonio, F., Volante, M., Pasini, D., Chiarugi, P., Giordano, S., & Corso, S.
- Affiliations
- Candiolo Cancer Institute (IT)
- University of Florence (IT)
- European Institute of Oncology (IT)
- University of Pisa (IT)
- University of Milan (IT)
- Ospedale San Luigi Gonzaga (IT)
- Tumour Institute of Tuscany (IT)
- Corresponding author
- Giordano, Silvia
- Corso, Simona
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 28
- Issue
- 6
- Pages
- 848-865.e6
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2889488326
- Cited by
- 299
- References
- 65
- Citations by year
- 2026: 29 · 2025: 47 · 2024: 26 · 2023: 40 · 2022: 48 · 2021: 45 · 2020: 44 · 2019: 19 · 2018: 1
- FWCI
- 8.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, other-oa)
- Florence Research (University of Florence) (submittedVersion)
- Funders
- University of Torino
- Fondo Ricerca Locale
- PROGETTO ATENEO/Compagnia San Paolo
- Italian Association for Cancer Research (20210)
- Fondazione Piemontese per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- lactate secretion, adaptive drug resistance, MET, EGFR, tyrosine kinase inhibitors, cancer-associated fibroblasts, hepatocyte growth factor, NF-κB signaling, tumor microenvironment, glycolysis, lung cancer
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, Glycolysis, Humans, Lung Neoplasms, Mice, Inbred NOD, Hepatocyte Growth Factor, Drug Resistance, Neoplasm, Lactic Acid, Proto-Oncogene Proteins c-met, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Tumor Microenvironment, ErbB Receptors
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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