Abstract
Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as “oncogene addiction”. A new generation of drugs that selectively target such “driver oncogenes” manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an “oncogenic driver” and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.
Highlights
Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as ―oncogene addiction‖ that is exemplified by the BCR-ABL fusion gene in chronic myeloid leukemia as well as by mutant forms of the epidermal growth factor receptor (EGFR) gene and by the EML4-anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC).A new generation of drugs that selectively target such ―driver oncogenes‖ and which include tyrosine kinase inhibitors (TKIs) has shown a therapeutic efficacy greater than that of conventional chemotherapy in individuals with these specific molecular alterations [1,2]
The binding of its ligand—the hepatocyte growth factor (HGF)—to MET results in tyrosine phosphorylation of the receptor and activation of downstream signaling pathways mediated by phosphoinositide 3-kinase (PI3K) and AKT, by signal transducer and activator of transcription 3 (STAT3), or by RAS and mitogen-activated protein kinase (MAPK)
To investigate the biological impact of MET amplification or mutation, we have examined the effects of a MET-TKI and of a small interfering RNA specific for MET mRNA on cell survival and signal transduction in NSCLC cells with or without such genetic alterations of MET [12]
Summary
Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as ―oncogene addiction‖ that is exemplified by the BCR-ABL fusion gene in chronic myeloid leukemia as well as by mutant forms of the epidermal growth factor receptor (EGFR) gene and by the EML4-ALK fusion gene in non-small cell lung cancer (NSCLC). Whereas normal activation of MET is essential for wound healing and embryonic development [3,4], excessive activation of MET signaling in a subset of advanced cancers [5,6,7,8,9] results in the up-regulation of cell proliferation, motility, migration, and invasion [3,10] Such aberrant MET signaling potentially arises from genetic alteration or dysregulation of MET [11], the target potential of MET alterations including polysomy, gene amplification, and gene mutation has not been well established
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