FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers in vitro

Mol Oncol. 2018 Jun;12(7):993-1003. doi: 10.1002/1878-0261.12194. Epub 2018 May 29.


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 in vitro 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.

Keywords: FGFR2 amplification; colorectal cancer; gastric cancer; regorafenib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Gene Amplification*
  • Humans
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use*
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics*
  • Signal Transduction
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Phenylurea Compounds
  • Pyridines
  • regorafenib
  • Receptor, Fibroblast Growth Factor, Type 2