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

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 c...

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Detalles Bibliográficos
Autores principales: Cha, Yongjun, Kim, Hwang‐Phill, Lim, Yoojoo, Han, Sae‐Won, Song, Sang‐Hyun, Kim, Tae‐You
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026866/
https://www.ncbi.nlm.nih.gov/pubmed/29573334
http://dx.doi.org/10.1002/1878-0261.12194
Descripción
Sumario: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.