Abstract
Abstract Purpose Regorafenib is an orally bioavailable, small molecular multikinase inhibitor of VEGFR, PDGFR, FGFR, KIT, RET, BRAF, BRAFV600E, CRAF, and TIE2. Although regorafenib has demonstrated survival benefits in patients with metastatic colorectal and gastrointestinal stromal tumors, there is no proven biomarker predicting sensitivity to regorafenib. We investigated preclinical activity of regorafenib in gastric and colorectal cancer cell-lines to identify genetic alterations associated with sensitivity to regorafenib. Methods Fourteen gastric cancer cell lines and 18 colorectal cancer cell lines were screened for regorafenib sensitivity with cell proliferation assays. We performed targeted exome and transcriptome sequencing of the cell lines to identify genetic alterations associated with sensitivity to regorafenib. Mechanisms of regorafenib sensitivity were investigated in regorafenib sensitive cell lines with immunoblotting and flow cytometry. Results Two gastric (SNU-16, KATO-III) and 1 colorectal (NCI-H716) cancer cells were sensitive to regorafenib with GI50 values of less than 1 μM. Mutation profiles and mRNA expression levels of regorafenib target molecules in regorafenib sensitive and insensitive cell lines demonstrated that amplification of FGFR2 was the only genetic alteration associated with in vitro sensitivity to regorafenib. FGFR2 amplified gastric (SNU-16, KATO-III) and colorectal (NCI-H716) cancer cell lines revealed activated signaling through FGFR2 pathway, and knock-down of FGFR2 with siRNA significantly repressed cellular growth rate and decreased sensitivity to regorafenib. Regorafenib effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules in dose-dependent manner selectively in FGFR2 amplified cells. In cell cycle analysis, regorafenib induced G1/S arrest (SNU-16, KATO-III) and apoptosis (NCI-H716), however no significant changes were seen in cell lines without FGFR2 amplification. Conclusions Signaling through FGFR2 pathway plays a key role in cellular growth and survival in FGFR2 amplified cancers. Regorafenib effectively abrogates activated FGFR2 signaling in FGFR2 amplified gastric and colorectal cancer cells, and therefore should be considered for integration into treatment in patients with FGFR2 amplified gastric and colorectal cancers. Citation Format: Yongjun Cha, Hwang-Phill Kim, Sae-won Han, Jiyeon Yun, Sang-Hyun Song, Tae-You Kim. FGFR2 amplification is predictive of sensitivity to regorafenib in gastric and colorectal cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5484. doi:10.1158/1538-7445.AM2015-5484
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