MCT1-dependent lactate recycling is a metabolic vulnerability in colorectal cancer cells upon acquired resistance to anti-EGFR targeted therapy.

Fiche publication

Date publication

juillet 2024

Journal

Cancer letters

Auteurs

Membres identifiés du Cancéropôle Est :
Dr BOIDOT Romain

Tous les auteurs :
Richiardone E, Al Roumi R, Lardinois F, Giolito MV, Ambroise J, Boidot R, Drotleff B, Ghesquière B, Bellahcène A, Bardelli A, Arena S, Corbet C

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/38964730

Résumé

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.