Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab

Abstract

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

Resveratrol Targets Urokinase-Type Plasminogen Activator Receptor Expression to Overcome Cetuximab-Resistance in Oral Squamous Cell Carcinoma

“…However, its clinical use is limited due to acquired drug resistance. A few previous studies have shown that activation of the EGFR-dependent pathways is regarded as the main cause of drug resistance 9,34,35 .…”

“…Therefore, it is of clinical importance to identify potential novel pathway(s) that mediate this acquired resistance phenotype to achieve better responses to cetuximab. In fact, recent studies have shown that the expression status of a glutamine transporter, solute carrier 1 family member 5 (SLC1A5), in human colorectal cancer patients dictates their response to cetuximab regardless of EGFR/KRAS mutational status, thus highlighting the importance of currently unknown/unrecognized novel molecular pathways driving cetuximab resistance 8,9 . Moreover, inhibiting SLC1A5 significantly enhanced the inhibitory efficacy of cetuximab, suggesting that unknown molecular mechanism(s) may be involved in other human malignancies such as cetuximab-resistant SCC of the oral cavity.…”

Combined blockade of EGFR and glutamine metabolism in preclinical models of colorectal cancer

“…Thus, V-9302 may represent a superior treatment strategy for CRC. A recent paper reports treatment of CRC by combining EGFR-inhibition by cetuximab with inhibition of SLC1A5 through either shRNA knockdown or pharmacological inhibition by l -γ-glutamyl- p -nitroanilide (GPNA) [ 52 ]. The authors observed enhanced efficacy and sensitization of resistant tumors with the combination in vitro and in vivo [ 52 ].…”

“…A recent paper reports treatment of CRC by combining EGFR-inhibition by cetuximab with inhibition of SLC1A5 through either shRNA knockdown or pharmacological inhibition by l -γ-glutamyl- p -nitroanilide (GPNA) [ 52 ]. The authors observed enhanced efficacy and sensitization of resistant tumors with the combination in vitro and in vivo [ 52 ]. Building upon these promising results and in view of the 100-fold improvement in potency of V-9302 over GPNA [ 51 ], combination therapy with V-9302 and EGFR-targeted antibodies may result in even further improved efficacy.…”

CRIP1 cooperates with BRCA2 to drive the nuclear enrichment of RAD51 and to facilitate homologous repair upon DNA damage induced by chemotherapy

“…Western blotting, immunoprecipitation, and immunofluorescence assays were performed as described previously using specific antibodies listed in Supplementary Table S2 [ 39 , 40 ]. Quantitative real-time PCR was performed using the SYBR Green I Master kit (Roche, Basel, Switzerland) with a LightCycler 480 system as described previously [ 39 , 41 ].…”