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Fibroblast growth factor receptor 3-mediated reactivation of ERK signaling promotes head and neck squamous cancer cell insensitivity to MEK inhibition

Authors
 Myung Jin Ban  ;  Hyung Kwon Byeon  ;  Yeon Ju Yang  ;  Sojung An  ;  Jae Wook Kim  ;  Ji‐Hoon Kim  ;  Da Hee Kim  ;  Jaemoon Yang  ;  Hyunjung Kee  ;  Yoon Woo Koh 
Citation
 Cancer Science, Vol.109(12) : 3816-3825, 2018 
Journal Title
 Cancer Science 
ISSN
 1347-9032 
Issue Date
2018
Keywords
MAP kinase signaling system ; MEK inhibition ; fibroblast growth factor receptor ; head and neck cancer ; receptor cross-talk
Abstract
Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) has been a longstanding challenge for head and neck oncologists, and current treatments still have limited efficacy. ERK is aberrantly overexpressed and activated in HNSCC. Herein, we aimed to investigate the cause of the limited therapeutic effect of selumetinib, a selective inhibitor of MEK in HNSCC, as MEK/ERK reactivation inevitably occurs. We assessed the effects of combining selumetinib with fibroblast growth factor receptor 3 (FGFR3) inhibitor (PD173074) on tumor growth. Selumetinib transiently inhibited MAPK signaling and reactivated ERK signaling in HNSCC cells. Rebound in the ERK and Akt pathways in HNSCC cells was accompanied by increased FGFR3 signaling after selumetinib treatment. Feedback activation of FGFR3 was a result of autocrine secretion of the FGF2 ligand. The FGFR3 inhibitor PD173074 prevented MAPK rebound and sensitized the response of HNSCC cells to selumetinib. These results provided rational therapeutic strategies for clinical studies of this subtype of patients that show a poor prognosis with selumetinib. Our data provide a rationale for combining a MEK inhibitor with inhibitors of feedback activation of FGFR3 signaling in HNSCC cells. ERK rebound as a result of the upregulation of FGFR3 and the ligand FGF2 diminished the antitumor effects of selumetinib, which was overcome by combination treatment with the FGFR3 inhibitor.
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DOI
10.1111/cas.13839
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
고윤우(Kho, Yoon Woo)
기현정(Kee, Hyun Jung) ORCID logo https://orcid.org/0000-0003-4350-1852
양재문(Yang, Jae Moon) ORCID logo https://orcid.org/0000-0001-7365-0395
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/167159
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