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

• Published in: Molecular oncology 2018-06, Vol.12 (7), p.993-1003
• Main Authors: Cha, Yongjun, Kim, Hwang‐Phill, Lim, Yoojoo, Han, Sae‐Won, Song, Sang‐Hyun, Kim, Tae‐You
• Format: Article
• Language: English
• Subjects: Antimitotic agents; Antineoplastic agents; Aprotinin; Colorectal cancer; FGFR2 amplification; Fibroblast growth factors; gastric cancer; Genetic aspects; Prognosis; regorafenib
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12194

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. Survival benefits have been seen in patients with metastatic colorectal and gastrointestinal stromal tumours when treated with regorafenib, but a biomarker predicting regorafenib sensitivity remains elusive. We found that amplification of fibroblast growth factor receptor 2 (FGFR2) was associated with regorafenib sensitivity in many colorectal and gastric cancer cell lines. Regorafenib also blocks FGFR2 signalling and displays antitumor activity in mice xenographs from SNU‐16 cells. Therefore, regorafenib is a potential candidate for treatments against FGFR2‐amplified colorectal and gastric cancers.