Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer

Abstract

Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation-driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer. (Cancer Res 2006; 66(1): 283-9)

Malignant melanoma: genetics and therapeutics in the genomic era

“…Accordingly, increased c-MET expression has been observed in metastatic melanoma (Natali et al 1993), and copy number gain of the c-MET locus at 7q33-qter seems to be a late event in melanoma progression (Wiltshire et al 1995;Bastian et al 1998). However, similar to EGFR above, neither focal MET amplifications nor activating MET point mutations have been detected in melanoma, although both have been observed in other human cancers Schmidt et al 1997;Kong-Beltran et al 2006;Smolen et al 2006). However, several lines of experimental and functional evidence support a causal role for MET signaling in human melanoma.…”

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

“…Moreover, it is notable that all three of these mechanisms of MET/MET dysregulation have been documented in non-small cell lung cancer (NSCLC; refs. [19][20][21][22]. Early studies established that MET can be overexpressed or activated [as measured by phosphorylation of the catalytic domain as well as juxtamembrane (JM) domain], or the gene mutated (in the semaphorin or JM domains) and/or amplified in lung cancer.…”

“…Using NSCLC tissues and cell lines, we (37) and Kong-Beltran and colleagues (22) functionally characterized tumor-specific somatic intronic MET mutations, which immediately flank exon 14 (22). Exon 14 was found to encode the JM domain and Y1003 residue that serves as the binding site for casitas B-lineage lymphoma (CBL), the E3 ubiquitin ligase that controls MET turnover (22).…”

“…Exon 14 was found to encode the JM domain and Y1003 residue that serves as the binding site for casitas B-lineage lymphoma (CBL), the E3 ubiquitin ligase that controls MET turnover (22). In each case of MET exon 14 skipping, confirmed by reverse transcriptase polymerase chain reaction, the result was a decrease in the ubiquitination of MET and consequent delayed receptor downregulation after stimulation with HGF.…”

From Tpr-Met to Met, tumorigenesis and tubes

“…Naturally occurring somatic mutants of the Met receptor, which lead to loss of the Cbl TKB-binding site, have been identified in human lung cancers and, as a consequence, these receptors are poorly ubiquitinated and not targeted for degradation (Kong-Beltran et al, 2006) (Figure 3). In a similar manner, the loss of the direct Cbl TKB-binding site in the CSF-1R (Mancini et al, 2002), as well as the loss of Cbl recruitment to the Kit receptor (Herbst et al, 1995), results in enhanced transforming activity.…”