The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma

Tanguy Y. Seiwert, Ramasamy Jagadeeswaran, Leonardo Faoro, Varalakshmi Janamanchi, Vidya Nallasura, Mohamed El Dinali, Soheil YaIa, Rajani Kanteti, Ezra E.W. Cohen, Mark W. Ungen, Leslie Martin, Soundararajan Krishnaswamy, Andres Klein-Szanto, James G. Christensen, Everett E. Vokes, Ravi Salgia

Research output: Contribution to journalArticlepeer-review

Abstract

Recurrent/metastatic head and neck cancer remains a devas- tating disease with insufficient treatment options. We investi- gated the MET receptor tyrosine kinase as a novel target for the treatment of head and neck squamous cell carcinoma (HNSCC). MET/phosphorylated MET and HGF expression was analyzed in 121 tissues (HNSCC/normal) by immunohisto- chemistry, and in 20 HNSCC cell lines by immunoblotting. The effects of MET inhibition using small interfering RNA/two small-molecule inhibitors (SU11274/PF-2341066) on signaling, migration, viability, and angiogenesis were determined. The complete MET gene was sequenced in 66 head and neck cancer tissue samples and eight cell lines. MET gene copy number was determined in 14 cell lines and 23 tumor tissues. Drug combinations of SU11274 with cisplatin or erlotinib were tested in SCC35/HN5 cell lines. Eighty-four percent of the HNSCC samples showed MET overexpression, whereas 18 of 20 HNSCC cell lines (90%) expressed MET. HGF overexpression was present in 45% of HNSCC. MET inhibition with SU11274/ PF-2341066 abrogated MET signaling, cell viability, motility/ migration in vitro, and tumor angiogenesis in vivo. Mutational analysis of 66 tumor tissues and 8 cell lines identified novel mutations in the semaphorin (T230M/E168D/N375S), juxta- membrane (T1010I/R988C), and tyrosine kinase (T1275I/ V1333I) domains (incidence: 13.5%). Increased MET gene copy number was present with >10 copies in 3 of 23 (13%) tumor tissues. A greater-than-additive inhibition of cell growth was observed when combining a MET inhibitor with cisplatin or erlotinib and synergy may be mediated via erbB3/AKT signaling. MET is functionally important in HNSCC with prominent overexpression, increased gene copy number, and mutations. MET inhibition abrogated MET functions, including proliferation, migration/motility, and angiogenesis. MET is a promising, novel target for HNSCC and combination approaches with cisplatin or EGFR inhibitors should be explored.

Original languageEnglish (US)
Pages (from-to)3021-3031
Number of pages11
JournalCancer Research
Volume69
Issue number7
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma'. Together they form a unique fingerprint.

Cite this