Abstract
<div>Abstract<p>BIM (BCL2L11) is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGF receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in <i>EGFR</i>-mutant forms of non–small cell lung cancer (NSCLC). Notably, a <i>BIM</i> deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the proapoptotic isoform required for the EGFR-TKIs gefitinib and erlotinib and therefore conferring an inherent drug-resistant phenotype. Indeed, patients with NSCLC, who harbored this host <i>BIM</i> polymorphism, exhibited significantly inferior responses to EGFR-TKI treatment than individuals lacking this polymorphism. In an attempt to correct this response defect in the resistant group, we investigated whether the histone deacetylase (HDAC) inhibitor vorinostat could circumvent EGFR-TKI resistance in <i>EGFR</i>-mutant NSCLC cell lines that also harbored the <i>BIM</i> polymorphism. Consistent with our clinical observations, we found that such cells were much less sensitive to gefitinib-induced apoptosis than <i>EGFR</i>-mutant cells, which did not harbor the polymorphism. Notably, vorinostat increased expression in a dose-dependent manner of the proapoptotic BH3 domain-containing isoform of BIM, which was sufficient to restore gefitinib death sensitivity in the <i>EGFR</i> mutant, EGFR-TKI–resistant cells. In xenograft models, while gefitinib induced marked regression via apoptosis of tumors without the <i>BIM</i> polymorphism, its combination with vorinostat was needed to induce marked regression of tumors with the <i>BIM</i> polymorphism in the same manner. Together, our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in cases of <i>EGFR</i>-mutant NSCLC where resistance to EGFR-TKI is associated with a common <i>BIM</i> polymorphism. <i>Cancer Res; 73(8); 2428–34. ©2013 AACR</i>.</p></div>
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