Several driver oncogenes, including
EGFR mutations, ALK rearrangement, ROS-1 rearrangement, and RET rearrangement, have been identified in lung adenocarcinoma. EGFR tyrosine kinase inhibitors (TKIs) and ALK-TKIs have been approved for lung cancer with
EGFR activating mutations and ALK rearrangements, respectively. In addition, many targeted drugs for other oncogenic drivers are also being evaluated for efficacy in clinical trials. EGFR-TKIs and ALK-TKIs show dramatic therapeutic efficacy against lung cancer with
EGFR mutation and ALK rearrangement, respectively. However, the responders almost invariably acquire resistance to EGFR-TKIs within several years. The representative mechanism is a secondary mutation in the target. A new generation of TKIs, which inhibit secondary mutations, has been developed and evaluated for efficacy in clinical trials. Apoptosis resistance is another important mechanism of TKI resistance.
BIM polymorphism is associated with EGFR-TKI resistance in
EGFR mutant lung cancer. We found that a HDAC inhibitor, vorinostat, could overcome EGFR-TKI resistance associated with
BIM polymorphism. According to this observation, we are currently evaluating the safety and efficacy of treatment with EGFR-TKI and vorinostat in an investigator initiated trial (VICTORY-J).
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