Molecular mechanism of EGFR-TKI resistance

Abstract

Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However. 25-30% of patients with EGFRmu show intrinsic resistance, and even responders invariably acquire resistance to EGFR-TKIs. Two mechanisms, second-site T790M point mutation in EGFR and MET amplification, which contribute to acquired resistance to EGFR-TKIs have been reported. T790M secondary mutation and MET amplification are found in approximately 50% and 20%. respectively, of patients acquiring resistance to EGFR-TKIs. However, the mechanisms of intrinsic resistance and the other 30% of cases of acquired resistance are still unknown. We recently reported hepatocyte growth factor (HGF) induced resistance as the third mechanism of EGFR-TKI resistance. HGF, produced by either cancer cells or host fibroblasts, induced resistance by restoring PI3K/Akt path-way via MET, independenty of ErbB3. In addition, inhibitors of HGF-MET successfully overcame HGF-induced resistance to EGFR-TKIs, indicating the importance of HGF-MET signaling as a considerable target for more successful treatment with EGFR-TKIs. © 2009 The Japan Lung Cancer Society.