Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer

Kenichi Suda, Isao Murakami, Tatsuya Katayama, Kenji Tomizawa, Hirotaka Osada, Yoshitaka Sekido, Yoshihiko Maehara, Yasushi Yatabe, Tetsuya Mitsudomi
Clinical Cancer Research 2010 November 15, 16 (22): 5489-98

PURPOSE: In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens.

EXPERIMENTAL DESIGN: Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib-refractory tumors were analyzed.

RESULTS: HCC827ER developed MET amplification, and clinically relevant resistance occurred at ≥4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib-refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib-refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (<4-fold), and in only 8% (1 of 13) of tumors with MET amplification (≥4-fold).

CONCLUSIONS: These results indicate a reciprocal and complementary relationship between T790M and MET amplification and the necessity of concurrent inhibition of both for further improving patient outcomes.


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