Amplification of <i>MET</i> may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752

TLDR

Molecular targeted therapy succeeds when tumors depend on the drug target, so preclinical methods are needed to identify such “oncogene‑addicted” subsets, as exemplified by MET, whose constitutive activation in amplified gastric cancers drives survival and invasion. Gastric cancer cells with high‑level MET amplification undergo massive apoptosis with PHA‑665752, whereas non‑amplified lines are resistant, indicating that MET amplification defines a highly sensitive epithelial cancer subset suitable for clinical trials of MET inhibitors.

Abstract

The success of molecular targeted therapy in cancer may depend on the selection of appropriate tumor types whose survival depends on the drug target, so-called “oncogene addiction.” Preclinical approaches to defining drug-responsive subsets are needed if initial clinical trials are to be directed at the most susceptible patient population. Here, we show that gastric cancer cells with high-level stable chromosomal amplification of the growth factor receptor MET are extraordinarily susceptible to the selective inhibitor PHA-665752. Although MET activation has primarily been linked with tumor cell migration and invasiveness, the amplified wild-type MET in these cells is constitutively activated, and its continued signaling is required for cell survival. Treatment with PHA-665752 triggers massive apoptosis in 5 of 5 gastric cancer cell lines with MET amplification but in 0 of 12 without increased gene copy numbers ( P = 0.00016). MET amplification may thus identify a subset of epithelial cancers that are uniquely sensitive to disruption of this pathway and define a patient group that is appropriate for clinical trials of targeted therapy using MET inhibitors.