Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab. Issue 12 (9th February 2018)

• Record Type: Journal Article
• Authors: Ma, Huanrong; Wu, Zhenzhen; Peng, Jianjun; Li, Yang; Huang, Hongxiang; Liao, Yi; Zhou, Minyu; Sun, Li; Huang, Na; Shi, Min; Bin, Jianping; Liao, Yulin; Rao, Jinjun; Wang, Lin; Liao, Wangjun
• Is Part Of: International journal of cancer. Volume 142:Issue 12(2018)
• Page Start: 2578
• Page End: 2588
• Publication Date: 2018-02-09
• Subjects: colorectal cancer -- SLC1A5 -- EGFR -- cetuximab -- EGFR degradation -- nuclear EGFR; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31274
• Languages: English
• ISSNs: 0020-7136

Abstract

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. Abstract : What's new? Cetuximab is an anti‐EGFR drug that is a valuable adjunct therapy for metastatic colorectal cancer (mCRC). Unfortunately, many tumors develop resistance. In this study, the authors found that a glutamine‐transporter protein called SLC1A5 is overexpressed in these resistant mCRC cells, and that blocking SLC1A5 activity restores the efficacy of cetuximab. These results support SLC1A5 as a promising therapeutic target for reversing cetuximab resistance.