[en] Despite the implementation of personalized medicine, patients with metastatic CRC (mCRC) still have a dismal overall survival due to the frequent occurrence of acquired resistance mechanisms thereby leading to clinical relapse. Understanding molecular mechanisms that support acquired resistance to anti-EGFR targeted therapy in mCRC is therefore clinically relevant and key to improving patient outcomes. Here, we observe distinct metabolic changes between cetuximab-resistant CRC cell populations, with in particular an increased glycolytic activity in KRAS-mutant cetuximab-resistant CRC cells (LIM1215 and OXCO2) but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 and OXCO2 cells have the capacity to recycle glycolysis-derived lactate to sustain their growth capacity. This is associated with an upregulation of the lactate importer MCT1 at both transcript and protein levels. Pharmacological inhibition of MCT1, with AR-C155858, reduces the uptake and oxidation of lactate and impairs growth capacity in cetuximab-resistant LIM1215 cells both in vitro and in vivo. This study identifies MCT1-dependent lactate utilization as a clinically actionable, metabolic vulnerability to overcome KRAS-mutant-mediated acquired resistance to anti-EGFR therapy in CRC.
Disciplines :
Oncology
Author, co-author :
Richiardone, Elena ; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
Al Roumi, Rim; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
Giolito, Maria Virginia ; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium
Ambroise, Jérôme; Centre des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 54, B-1200, Brussels, Belgium
Boidot, Romain; Unit of Molecular Biology, Department of Biology and Pathology of Tumors, Georges-François Leclerc Cancer Center-UNICANCER, 21079, Dijon, France
Ghesquière, Bart ; Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium, Metabolomics Core Facility Leuven, Center for Cancer Biology, VIB, Leuven, Belgium
Bellahcene, Akeila ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Bardelli, Alberto; Department of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy
Arena, Sabrina ; Department of Oncology, University of Torino, Candiolo, TO, Italy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, TO, Italy. Electronic address: sabrina.arena@unito.it
Corbet, Cyril ; Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, Avenue Hippocrate 57, B1.57.04, B-1200, Brussels, Belgium. Electronic address: cyril.corbet@uclouvain.be
Language :
English
Title :
MCT1-dependent lactate recycling is a metabolic vulnerability in colorectal cancer cells upon acquired resistance to anti-EGFR targeted therapy.
This work was supported by research grants from the Fonds National de la Recherche Scientifique (F.R.S.-FNRS), the Belgian Foundation against Cancer, and the J. Maisin Foundation. The research leading to these results has also received funding from: AIRC under BRIDGE 2022-ID 27321 project (S.A.), MUR Dipartimento di Eccellenza 2023\u20132027 14586 DIORAMA (S.A.), Finanziamento dell'Unione Europea NextGeneration EU M4 C2 investimento 1.1.- PRIN 2022 PNRR P2022E3BTH (S.A.), Italian Ministry of Health, Ricerca Corrente 2024 (S.A.), AIRC under 5 per Mille 2018 - ID. 21091 program (A.Ba.); International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB) and AIRC (22795) (A.Ba.); AIRC under IG 2023 - ID. 28922 project (A.Ba.) and PRIN 2022 - Prot. 2022CHB9BA (A.Ba.). CC is a FNRS Research Associate. ER is a FNRS-FRIA PhD fellow. AB is a FNRS Research Director.This work was supported by research grants from the Fonds National de la Recherche Scientifique (F.R.S.-FNRS), the Belgian Foundation against Cancer, and the J. Maisin Foundation. The research leading to these results has also received funding from: AIRC under BRIDGE 2022-ID 27321 project (S.A.), MUR Dipartimento di Eccellenza 2023-2027 14586 DIORAMA (S.A.), Finanziamento dell\u2019Unione Europea NextGeneration EU M4 C2 investimento 1.1.- PRIN 2022 PNRR P2022E3BTH (S.A.), AIRC under 5 per Mille 2018 - ID. 21091 program (A.Ba.); International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB) and AIRC (22795) (A.Ba.); AIRC under IG 2023 - ID. 28922 project (A.Ba.) and PRIN 2022 - Prot. 2022CHB9BA (A.Ba.). CC is a FNRS Research Associate. ER is a FNRS-FRIA PhD fellow. AB is a FNRS Research Director.
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