Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas

Abstract

A metastatic cancer develops by accumulation of mutations in genes that control growth, survival and spreading. The latter genes have not yet been identi®ed. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosine kinase receptor for Scatter Factor, a cytokine that stimulates epithelial cell motility and invasiveness during embryogenesis and tissue remodeling. We identi®ed two somatic mutations: the Y1230C, known as a MET germline mutation which predisposes to hereditary renal cell carcinoma, and the Y1235D that is novel and changes a critical tyrosine, known to regulate MET kinase activity. The mutated MET receptors are constitutively active and confer an invasive phenotype to transfected cells. Interestingly, cells carrying the MET mutations are selected during metastatic spread: transcripts of the mutant alleles are highly represented in metastases, but barely detectable in primary tumors. These data indicate that cells expressing mutant MET undergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis. Oncogene (2000) 19, 1547 ± 1555.

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

“…This analysis not only explains the observed selectivity but also suggests that, aside from MET, no human kinase can be potently inhibited by SGX523. Also, these results, combined with the observations that MET catalytic activity tolerates mutation of Tyr 1248 and that mutations affecting this position have been identified in human tumors (28)(29)(30), suggest that missense mutation at codon 1,248 in the MET gene is a likely mechanism of resistance to inhibitors of the SGX523 class.…”

Silencing the MET oncogene leads to regression of experimental tumors and metastases

“…This suggests that the continuous expression of this oncogene, even in advanced phases of tumor progression, is so critical that gene amplification confers a selective advantage and it is thus stably acquired. Moreover, it has been shown that MET activating mutations, preferentially driving pathways responsible for promoting invasion and protection from apoptosis, are specifically selected during metastasis, in humans (Di Renzo et al, 2000).…”

Cross-talk between the proto-oncogenes Met and Ron

“…The Met receptor is expressed mainly in epithelial cells (Stoker et al, 1987;Di Renzo et al, 1991), but it has also been identi®ed in endothelial cells (Bussolino et al, 1992;Grant et al, 1993), in myoblasts (Anastasi et al, 1997), in cells of the hematopoietic system (Galimi et al, 1994;Nishino et al, 1995) and in spinal motor neurons (Ebens et al, 1996). Inappropriate activation of the HGF/Met pathway has been implicated in the onset and progression of a number of tumors and has been shown to promote the metastatic spread of neoplastic cells (Di Renzo et al, 1991Vande Woude et al, 1997;Giordano et al, 1997).…”

“…Inappropriate activation of the HGF/Met pathway has been implicated in the onset and progression of a number of tumors and has been shown to promote the metastatic spread of neoplastic cells (Di Renzo et al, 1991Vande Woude et al, 1997;Giordano et al, 1997). A more direct link between Met and cancer has been provided by the identi®cation of point mutations in the MET proto-oncogene in hereditary and sporadic papillary renal carcinomas (PRC mutations) .…”