MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients

Abstract

Background: MET amplification has been detected in approximately 20% of non-small-cell lung cancer patients (NSCLC) with epidermal growth factor receptor (EGFR) mutations progressing after an initial response to tyrosine kinase inhibitor (TKI) therapy.

Patients and methods: We analyzed MET gene copy number using FISH in two related NSCLC cell lines, one sensitive (HCC827) and one resistant (HCC827 GR6) to gefitinib therapy and in two different NSCLC patient populations: 24 never smokers or EGFR FISH-positive patients treated with gefitinib (ONCOBELL cohort) and 182 surgically resected NSCLC not exposed to anti-EGFR agents.

Results: HCC827 GR6-resistant cell line displayed MET amplification, with a mean MET copy number >12, while sensitive HCC827 cell line had a mean MET copy number of 4. In the ONCOBELL cohort, no patient had gene amplification and MET gene copy number was not associated with outcome to gefitinib therapy. Among the surgically resected patients, MET was amplified in 12 cases (7.3%) and only four (2.4%) had a higher MET copy number than the resistant HCC827 GR6 cell line.

Conclusions: MET gene amplification is a rare event in patients with advanced NSCLC. The development of anti-MET therapeutic strategies should be focused on patients with acquired EGFR-TKI resistance.

Figure 1.

Hybridization of MET/CEP7 probe set with specimens HCC827 (A) and HCC827 GR6 (B). On average four copies of MET signals (red) per cell were found in HCC827 while large clusters of MET signals were detected in all HCC827 GR6 nuclei.

Figure 2.

In the ONCOBELL cohort, the median MET mean gene copy number per cell was 2.91. Time to disease progression was 2.6 months in patients with mean MET gene copy number ≥2.91 (MET high copy number) and 2.2 months in individuals with mean MET gene copy number <2.91 (MET low copy number). This difference was not statistically significant (P = 0.6). Median survival was 18.7 months in patients with mean MET gene copy number ≥2.91 and 5.2 months in individuals with mean MET gene copy number <2.91. The difference was not statistically significant (P = 0.15).