Inhibition of SLC1A 5 sensitizes colorectal cancer to cetuximab

Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources importcould resensitize drug-resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutaminetransporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to cetuximab was signifi-cantly higher than in those of patients responded to cetuximab. Inhibition of SLC1A5 by shRNA-mediated gene silencing orpharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhancedthe inhibitory efficacy of cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitatedEGFR degradation through the ubiquitin-proteasome pathway, and decreased the expression of nuclear EGFR, both of whichmight have contribution to the improved response to cetuximab. This study provides the metabolic molecule SLC1A5 as apotential therapeutic target to increase the efficacy of cetuximab on CRC