Various molecular targeted anticancer drugs are often developed by targeting activated growth factor receptors that are expressed on plasma membrane of cancer cells. Expression of such active receptors on the cell surface is essential to limit the drug sensitivity to molecular targeted drugs in lung cancer cells and others. The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane-associated proteins that are involved in membrane-trafficking steps within the endocytotic network. Human SNX family proteins comprise about 34 proteins with wide range of biological functions, which play specialized and/or generalized roles in the regulation of protein trafficking, including endosomal trafficking of membrane receptors and transporters. SNX1 and SNX2 are components of the mammalian retromer complex. In this study, we show that the small-interfering RNA (siRNA)-mediated knockdown of SNX2 decreased the cell-surface localization of c-Met, but not that of EGFR, resulting in degradation of the c-Met protein. Knockdown of SNX2 markedly altered sensitivity to anticancer drugs targeting c-Met and EGFR through promotion of compensatory activation of the EGFR pathway in lung cancer cells. Furthermore, SNX2 knockdown also specifically decreased c-Met expression, and altered drug sensitivity to c-Met-targeted drug in gastric cancer cells. These findings suggest that SNX2 is a key protein that regulates c-Met-driven growth-signalling pathways, affecting the therapeutic efficacy of growth factor receptor-targeted drugs in lung and gastric cancer patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1199. doi:1538-7445.AM2012-1199