Abstract 3028: ERK signal suppression and sensitivity to CH5183284/Debio 1347, a selective FGFR inhibitor
Authors: Nakanishi Yoshito , Mizuno Hideaki , Sase Hitoshi , Fujii Toshihiko , Sakata Kiyoaki , Akiyama Nukinori , Aoki Yuko , Aoki Masahiro , Ishii Nobuya 
Published: July 2016

Drugs that target specific gene alterations have proven beneficial in the treatment of cancer. Because cancer cells have multiple resistance mechanisms, it is important to understand the downstream pathways of the target genes and monitor the pharmacodynamic markers associated with therapeutic efficacy. In a previous study, we analyzed the signaling pathway of an FGFR (fibroblast growth factor receptor) fusion kinases, FGFR3-BAIAP2L1. A Rat-2 cell line stably expressing FGFR3-BAIAP2L1 exhibited potent tumorigenic activity. Gene expression analysis revealed strong up-regulation of genes downstream of the MAPK pathway, and up-regulation of the MAPK pathway was validated by western blotting; in contrast, the PI3K/AKT pathway was not activated by FGFR3-BAIAP2L1. Therefore, we suggested that MAPK pathway activation is essential to the tumorigenic activity of FGFR3-BAIAP2L1. In this study, to generalize the MAPK pathway dependency of FGFR, we characterized the pathway modulation by CH5183284/Debio 1347, a selective FGFR inhibitor, in several FGFR genetically altered cancer cell lines, such as FGFR1 gene amplified, FGFR2 gene amplified or mutated, and FGFR3 gene mutated or rearranged cell lines. We performed a transcriptome analysis to characterize the response of various cancer cell lines to CH5183284/Debio 1347, a MEK inhibitor, or a PI3K inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the ERK gene signature was altered in several FGFR inhibitor-sensitive cell lines. Consistent with these findings, CH5183284/Debio 1347 suppressed phospho-ERK in every tested FGFR inhibitor-sensitive cell line. Because the MAPK pathway functions downstream of FGFR, we searched for a pharmacodynamic marker of FGFR inhibitor efficacy in a collection of cell lines with the ERK signature and identified dual-specificity phosphatase 6 (DUSP6) as a candidate marker. Suppression of DUSP6 protein level was also confirmed in mice xenograft models. Although a MEK inhibitor suppressed the MAPK pathway, most FGFR inhibitor-sensitive cell lines are insensitive to MEK inhibitors and we found potent feedback activation of several pathways via FGFR. We therefore suggest that FGFR inhibitors exert their effect by suppressing ERK signaling without feedback activation. In addition, DUSP6 may be a pharmacodynamic marker of FGFR inhibitor efficacy in FGFR-addicted cancers.

*CH5183284/Debio 1347 was discovered by Chugai Pharmaceutical Co., Ltd. and is being developed by Debiopharm International S.A. under an exclusive worldwide license.

Citation Format: Yoshito Nakanishi, Hideaki Mizuno, Hitoshi Sase, Toshihiko Fujii, Kiyoaki Sakata, Nukinori Akiyama, Yuko Aoki, Masahiro Aoki, Nobuya Ishii. ERK signal suppression and sensitivity to CH5183284/Debio 1347, a selective FGFR inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3028.