SRA

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 LIM1215 but not in KRAS-amplified resistant DiFi cells. We show that cetuximab-resistant LIM1215 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. 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. Overall design: To study the metabolic adaptation of CRC cells upon acquired resistance to cetuximab treatment, we used two human colon cancer cell lines LIM1215 and DiFi, initially cetuximab-sensitive (denoted as -S), and for which populations with acquired resistance (-R1 and -R2) had been previously established upon chronic exposure for several months with the drug (Misale et al Nature 2012). While DiFi-R cells harbored EGFR gene copy number reduction and KRAS gene amplification, LIM1215-R cells were reported to display KRAS activating mutations. We then carried out gene expression profiling analysis using RNA-seq data obtained from cetuximab-resistant (-R1 and -R2) and cetuximab-sensitive (-S) DiFi and LIM1215 CRC cells.