Open AccessFGFR 2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro
Author(s) -
Cha Yongjun,
Kim HwangPhill,
Lim Yoojoo,
Han SaeWon,
Song SangHyun,
Kim TaeYou
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12194
Subject(s) - regorafenib , cancer research , colorectal cancer , fibroblast growth factor receptor , medicine , cancer , biology , oncology , fibroblast growth factor , receptor
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 ( FGFR 2) was the only genetic alteration associated with in vitro sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR 2 and its downstream signaling molecules in a dose‐dependent manner and selectively in FGFR 2‐amplified cells. Regorafenib induced G1 arrest ( SNU ‐16, KATO ‐ III ) and apoptosis ( NCI ‐H716); however, no significant changes were seen in cell lines without FGFR 2 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 FGFR 2 signaling in FGFR 2‐amplified gastric and colorectal cancer and, therefore, might be considered for integration into treatment in patients with FGFR 2‐amplified gastric and colorectal cancers.