title: ERK Signal Suppression and Sensitivity to CH5183284/Debio 1347, a Selective FGFR Inhibitor.
abstract: 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. We performed a transcriptome analysis to characterize the response of various cancer cell lines to a selective fibroblast growth factor receptor (FGFR) inhibitor (CH5183284/Debio 1347), a mitogen-activated protein kinase kinase (MEK) inhibitor, or a phosphoinositide 3-kinase (PI3K) inhibitor. FGFR and MEK inhibition produced similar expression patterns, and the extracellular signal-regulated kinase (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 mitogen-activated protein kinase (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. 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.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan. nakanishiyst@chugai-pharm.co.jp.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mizuno
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sase
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Sakata
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Nukinori
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
mesh_terms: D001562:Benzimidazoles / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D011720:Pyrazoles / Q000008:administration & dosage*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D001562:Benzimidazoles; C000602562:CH5183284; D009363:Neoplasm Proteins; D011720:Pyrazoles; D017468:Receptors, Fibroblast Growth Factor; D051057:Proto-Oncogene Proteins c-akt