Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors

Abstract

Background: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC.Materials and methods: pAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells.Results: EGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied.Conclusions: Activated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients.cMET may be a target in treatment of NSCLC.

The Relationship Between Common EGFR, BRAF, KRAS Mutations and Prognosis in Advanced Stage Non-Small Cell Lung Cancer with Response to the Treatment in Turkey.

“…It was reported that KRAS mutation might have a role in prediction of 'de novo' resistance to EGFR-TKIs in a meta-analysis. 2,25 In our study, a 53-year old non-smoker woman with stage IV adenocarcinoma and KRAS exon 2 codon 61 deletion had 3 months of disease stabilization with second line erlotinib, however she had progression after 7 months. The effect of BRAF mutation on gefitinib response could not have been evaluated in ISEL study since none of the patients had BRAF mutation.…”

Cancer cells harboring MET gene amplification activate alternative signaling pathways to escape MET inhibition but remain sensitive to Hsp90 inhibitors

“…9,11,35 Indeed, in NSCLC, MET amplification and c-Met activation have been suggested as one means of escape from, or inherent insensitivity to, EGFR TKI. 8,[36][37][38] Amplified c-Met has been reported to drive the activity of EGFR family members and, conversely, mutated and amplified EGFR can drive c-Met activity. 24 Very recently, ligand-induced EGFR family kinase activation has been shown to confer initial resistance to c-Met TKI in MET-amplified gastric carcinoma cell lines, suggesting that, as is the case with other targeted kinases, escape from prolonged c-Met TKI exposure can readily occur.…”

The Role of MET Activation in Determining the Sensitivity to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

“…In particular, Engelman et al (6) showed that an MET inhibitor could restore cellular sensitivity to EGFR-TKIs. Furthermore, activated MET was found to be a marker of primary resistance to gefitinib in lung cancer patients, which suggests that MET inhibitors might be useful in these patients (11). These findings mean that cancer cells expressing activated MET prior to developing resistance can promptly use the MET pathway if EGFR signaling, which they are dependent on for survival, is blocked.…”