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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.
Ban, Myung Jin; Byeon, Hyung Kwon; Yang, Yeon Ju; An, Sojung; Kim, Jae Wook; Kim, Ji-Hoon; Kim, Da Hee; Yang, Jaemoon; Kee, Hyunjung; Koh, Yoon Woo.
Afiliação
  • Ban MJ; Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Cheonan, Korea.
  • Byeon HK; Department of Medicine, The Graduate School of Yonsei University, Seoul, Korea.
  • Yang YJ; Department of Otorhinolaryngology-Head and Neck Surgery, Korea University College of Medicine, Seoul, Korea.
  • An S; Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
  • Kim JW; Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
  • Kim JH; Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University College of Medicine, Cheonan, Korea.
  • Kim DH; Department of Otorhinolaryngology-Head and Neck Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea.
  • Yang J; Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.
  • Kee H; Department of Radiology, Yonsei University College of Medicine, Seoul, Korea.
  • Koh YW; Research Institute of Radiological Science, Yonsei University College of Medicine, Seoul, Korea.
Cancer Sci ; 109(12): 3816-3825, 2018 Dec.
Article em En | MEDLINE | ID: mdl-30343534
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Benzimidazóis / Resistencia a Medicamentos Antineoplásicos / Receptor ErbB-3 / Carcinoma de Células Escamosas de Cabeça e Pescoço / Neoplasias de Cabeça e Pescoço Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Pirimidinas / Benzimidazóis / Resistencia a Medicamentos Antineoplásicos / Receptor ErbB-3 / Carcinoma de Células Escamosas de Cabeça e Pescoço / Neoplasias de Cabeça e Pescoço Idioma: En Ano de publicação: 2018 Tipo de documento: Article