Targeting MET Amplification as a New Oncogenic Driver

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.

Figure 1

(A) Schematic comparison of gene amplification and polysomy. The ratio of the copy number for the target gene to that for the centromeric portion of the chromosome distinguishes an increased copy number of the target gene attributable to gene amplification from that resulting from extra copies of the chromosome (polysomy). (B) FISH analysis of a gastric cancer cell line (HSC58) positive for MET amplification. The image shows a single cancer cell, with green and red signals corresponding to CEP7 (CEN7p) and the MET locus, respectively.