MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling

Engelman, J. A., et al. 2007. Science. 316, 1039-1043

Speaker: Jeng-Liang Tsai (蔡政良)                  Time: 13:00~14:00, Oct. 24, 2007

Commentator: Dr. Yi-Ching Wang (王憶卿博士)      Place: Room 601

Abstract:

Lung cancer is a deadly disease with high mortality and morbidity. Approximately 85% of these cases are non-small cell lung cancer (NSCLC) with the rest being small cell lung cancer (SCLC). Like normal cells, lung cancer cells express receptor tyrosine kinases. The difference is that these receptors may be overexpressed or mutated leading to increased activation. The epidermal growth factor receptor (EGFR) kinase has emerged as an attractive therapeutic target for patients with NSCLC¹. Gefitinib, the EGFR kinase inhibitor, is effective in treating for lung cancers with EGFR activating mutations. However, these tumors invariably develop drug resistance. In about 50% of these cases, resistance is due to the occurrence of a secondary mutation in EGFR (T790M)². The mechanisms that contribute to resistance in the remaining tumors are unknown. In this study, the authors generated gefitinib resistant lung cancer cells (HCC827 GR) and found MET amplification in these resistant cells. MET is a receptor tyrosine kinase whose activation by hepatocyte growth factor can lead to transformation and tumorigenicity³. Notably, MET amplification leads to persistent activation of PI3K/Akt signaling in the presence of gefitinib by maintaining ERBB3 phosphorylation. These findings suggest that the observed resistance in HCC827 GR cells is mediated by increased MET signaling. Therefore, combination therapies with MET kinase inhibitors and EGFR inhibitors should be considered for patients whose tumors have become resistant to gefitinib. More generally, these studies suggest that ERBB3-mediated activation of PI3K/Akt might be a common feature of cancer cells that have MET amplification.

References:

1.         Janne, P. A., Engelman, J. A. & Johnson, B. E. Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. J Clin Oncol 23, 3227-34 (2005).

2.         Kosaka, T. et al. Analysis of epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res 12, 5764-9 (2006).

3.         Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4, 915-25 (2003).