HDAC Inhibition Circumvents EGFR Tyrosine Kinase Inhibitor Resistance Due to BIM Polymorphism 

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Upregulation of BIM (BCL2L11), a proapoptotic member of the BCL2 protein family, is required for induction of apoptosis by EGFR tyrosine kinase inhibitors in EGFR-mutant forms of non–small cell lung cancer (NSCLC). A BIM deletion polymorphism occurs naturally in approximately 13% of East Asian individuals, impairing the production of the proapoptotic isoform and conferring a drug-resistant phenotype. In a study reported in Cancer Research, Nakagawa and colleagues showed that the histone deacetylase (HDAC) inhibitor vorinostat (Zolinza) could circumvent EGFR tyrosine kinase inhibitor resistance in EGFR-mutant NSCLC cell lines with this BIM polymorphism.

Cells with the BIM polymorphism were much less sensitive to gefitinib-induced apoptosis than EGFR-mutant cells not harboring the polymorphism. Vorinostat increased expression of the proapoptotic isoform of BIM in a dose-dependent manner and restored sensitivity to gefitinib in the EGFR-mutant, EGFR tyrosine kinase inhibitor–resistant cells. In xenograft models, the combination of vorinostat and gefitinib was necessary to induce regression of tumors with the BIM polymorphism similar to that seen with gefitinib alone in tumors without the polymorphism.

The investigators concluded, “Together, our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR [tyrosine kinase inhibitors] in cases of EGFR-mutant NSCLC where resistance to EGFR [tyrosine kinase inhibitors] is associated with a common BIM polymorphism.” ■

Nakagawa T, et al: Cancer Res 73:2428-2434, 2013. ■




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