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Involvement of Notch‐1 in Resistance to Regorafenib in Colon Cancer Cells
Author(s) -
Mirone Giovanna,
Perna Stefania,
Shukla Arvind,
Marfe Gabriella
Publication year - 2016
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.25206
Subject(s) - regorafenib , notch signaling pathway , cancer research , jag1 , stromal cell , biology , microbiology and biotechnology , growth factor receptor , colorectal cancer , protein kinase b , signal transduction , cancer , genetics
Regorafenib, an oral small‐molecule multi kinase inhibitor, is able to block Vascular Endothelial Growth Factor Receptors (VEGFR‐1, 2, and 3), Platelet‐Derived Growth Factor Receptors (PDGF), Fibroblast Growth Factor (FGF) receptor 1, Raf, TIE‐2, and the kinases KIT, RET, and BRAF. Different studies have displayed its antitumor activity in several cancer models (both in vitro and in vivo), particularly in colorectal and gastrointestinal stromal cancers. The mechanism of resistance to regorafenib is largely unknown. In our investigation, we have generated regorafenib‐resistant SW480 cells (Reg‐R‐SW480 cells) by culturing such cells with increasing concentration of regorafenib. Examination of intracellular signaling found that Akt signaling was activated in Reg‐R‐SW480 cells but not in wild–type SW480 cells, after regorafenib treatment as measured by Western Blot. The Notch pathway is a fundamental signaling system in the development and homeostasis of tissues since it regulates different cellular process such as proliferation, differentiation, and apoptosis and it can be a potential driver of resistance to a wide array of targeted therapies. In this study, we found that Notch‐1 was significantly up‐regulated in resistant tumor cells as well as HES1 and HEY. Additionally, inhibition of Notch‐1 in resistant cells partially restored sensitivity to regorafenib treatment in vitro. Collectively, these data suggest a key role of Notch‐1 in mediating the resistant effects of regorafenib in colorectal cancer cells, and also provide a rationale to improve the therapeutic efficacy of regorafenib. J. Cell. Physiol. 231: 1097–1105, 2016. © 2015 Wiley Periodicals, Inc.