Therapeutic Strategies for Overcoming Resistance to Egfr-Tki and Alk-Tki by Inhibition of Hsp90 or Hdac

Recent advances in molecular biology have led to the identification of new molecular targets, such as EGFR mutations and EML4-ALK fusion gene, in lung cancer. Dramatic response has been achieved with EGFR-TKI (gefitinib and erlotinib) and an ALK-TKI (crizotinib) in lung cancer expressing corresponding targets. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major clinically relevant mechanisms of acquired resistance to EGFR-TKI are gatekeeper mutation, Met amplification, and increased expression of HGF. Additionally, we reported that EGF receptor ligands activate EGFR as a bypass signal and induce crizotinib resistance in EML4-ALK lung cancer cells. Hsp90 is a molecular chaperone that plays a central role in regulating the correct folding, stability of client proteins, including mutant EGFR, EML4-ALK, and also Met, wild-type EGFR which cause ligand triggered resistance to TKIs. Hsp90 inhibition is therefore thought to be a promising strategy for overcoming resistance of EGFR-TKI and ALK-TKI. Moreover, a BIM deletion polymorphism was reported to be a novel mechanism of resistance to EGFR-TKI. BIM is a BH3-only proapoptotic protein, and its upregulation is required for apoptosis induction by EGFR-TKI. Notably, a BIM deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the proapoptotic isoform required for the EGFR-TKI therefore conferring an inherent drug-resistant phenotype. We reported HDAC inhibitor vorinostat could increase expression of the proapoptotic BH3 domain-containing isoform of BIM, which was sufficient to restore gefitinib death sensitivity in the EGFR mutant, EGFR-TKI resistant cells. Our results show that HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in cases of EGFR mutant lung cancer where resistance to EGFR-TKI is associated with a common BIM polymorphism.