Journal
MOLECULAR ONCOLOGY
Volume 12, Issue 7, Pages 993-1003Publisher
WILEY
DOI: 10.1002/1878-0261.12194
Keywords
colorectal cancer; FGFR2 amplification; gastric cancer; regorafenib
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Funding
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute - Ministry of Health Welfare [HI14C1277, HI13C2096]
- SNUH Research Fund [0320150440]
- Ministry of Science, ICT & Future Planning [2016M3A9B6026918]
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Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, no proven biomarker has been identified for predicting sensitivity to regorafenib. Here, we investigated preclinical activity of regorafenib in gastric and colorectal cancer cells to identify genetic alterations associated with sensitivity to regorafenib. Mutation profiles and copy number assays of regorafenib target molecules indicated that amplification of fibroblast growth factor receptor 2 (FGFR2) was the only genetic alteration associated with invitro sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules in a dose-dependent manner and selectively in FGFR2-amplified cells. Regorafenib induced G1 arrest (SNU-16, KATO-III) and apoptosis (NCI-H716); however, no significant changes were seen in cell lines without FGFR2 amplification. In SNU-16 mice xenografts, regorafenib significantly inhibited tumor growth, proliferation, and FGFR signaling compared to treatment with control vehicle. Regorafenib effectively abrogates activated FGFR2 signaling in FGFR2-amplified gastric and colorectal cancer and, therefore, might be considered for integration into treatment in patients with FGFR2-amplified gastric and colorectal cancers.
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