Involvement of Notch-1 in Resistance to Regorafenib in Colon Cancer Cells

Abstract

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.

Colorectal carcinogenesis: Insights into the cell death and signal transduction pathways: A review

“…It was demonstrated that Notch signalling is significantly upregulated in SW480 cells that are resistant to the experimentally-generated Regorafenib drug, a multi-kinase inhibitor. Interestingly, the inhibition of Notch signalling in resistant cells restored their sensitivity to Regorafenib, thus suggesting the important role of Notch in promoting resistance to chemotherapeutic drugs[ 135 ]. The dysregulation of Notch signalling in colon cancer metastasis has been studied in detail[ 136 ].…”

Overexpression of Notch3 and pS6 Is Associated with Poor Prognosis in Human Ovarian Epithelial Cancer

“…Although the roles of Notch3 and S6K in cancer development have been studied, no study has been carried out to combine the expression of Notch3 and S6K in relation to the prognosis of human ovarian epithelial cancer. It is known that Notch3 and S6K may complement their common functions in cancer development, but their roles in specific tumors are unique and context-dependent [ 8 – 11 ]. In the present study, we first investigated the expression of Notch3 and S6K in human ovarian epithelial cancer, to verify their expression related to clinicopathological features and prognosis in human ovarian epithelial cancer and to further evaluate their potential value as biological markers of aggressiveness in ovarian cancer, with the goal of improving the management of ovarian cancer patients.…”

Tumor Sidedness and Enriched Gene Groups for Efficacy of First-line Cetuximab Treatment in Metastatic Colorectal Cancer

“…Moreover, NOTCH1-high expression had multivariable associations with poor outcomes in CRC (16)(17)(18)(19). NOTCH1 mediates the resistant effects of regorafenib in colorectal cancer cells (20). It has also been shown that NOTCH1 expression is a detrimental prognostic factor in patients with mCRC who receive chemotherapy plus the anti-VEGF antibody bevacizumab (21).…”