Searching across hundreds of databases
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.
Pubmed ID: 30174307 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This unknown targets Rabbit IgG Control
View all literature mentionsThis monoclonal targets Vinculin antibody produced in mouse
View all literature mentionsThis polyclonal targets H3K9me3
View all literature mentionsThis unknown targets H3K36me3
View all literature mentionsThis polyclonal targets H3K27ac
View all literature mentionsThis unknown targets H3K27me3
View all literature mentionsThis unknown targets H3K4me3
View all literature mentionsThis polyclonal targets H3K4me1
View all literature mentionsThis monoclonal targets Mouse Human Carbonic Anhydrase
View all literature mentionsThis monoclonal targets Human epidermal callus1
View all literature mentionsThis monoclonal targets EGFR (3H2094)
View all literature mentionsThis polyclonal targets EGFR (phospho Y1068) antibody
View all literature mentionsThis polyclonal targets ACTG1, ACTC1, ACTA1, ACTA2, ACTG2, ACTB
View all literature mentionsThis monoclonal targets LDH-B (Q-21)
View all literature mentionsThis monoclonal targets Genetic locus: RELA (human) mapping to 11q13.1; Rela (mouse) mapping to 19 A.
View all literature mentionsThis polyclonal targets NFKBIA
View all literature mentionsThis polyclonal targets Met (C-28)
View all literature mentionsThis monoclonal targets Glut1
View all literature mentionsThis monoclonal targets Hexokinase II
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis unknown targets Mouse IgG1 kappa Isotype Control FITC Clone MOPC-21
View all literature mentionsThis monoclonal targets Mouse Human CD326 (EpCAM) FITC Clone HEA-125
View all literature mentionsMulti paradigm numerical computing environment and fourth generation programming language developed by MathWorks. Allows matrix manipulations, plotting of functions and data, implementation of algorithms, creation of user interfaces, and interfacing with programs written in other languages, including C, C++, Java, Fortran and Python. Used to explore and visualize ideas and collaborate across disciplines including signal and image processing, communications, control systems, and computational finance.
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
scicrunch.org
