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- W4361952115 abstract "<div>Abstract<p><b>Purpose:</b> The <i>BIM</i> deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring <i>EGFR</i> mutations. Here, we investigated whether the <i>BIM</i> deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.</p><p><b>Experimental Design:</b> We used <i>EGFR</i>-mutated NSCLC cell lines, which were either heterozygous or homozygous for the <i>BIM</i> deletion polymorphism, to evaluate the effect of osimertinib <i>in vitro</i> and <i>in vivo</i>. Protein expression was examined by Western blotting. Alternative splicing of <i>BIM</i> mRNA was analyzed by RT-PCR.</p><p><b>Results:</b> <i>EGFR</i>-mutated NSCLC cell lines with the <i>BIM</i> deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage–dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous <i>BIM</i> deletion–positive cells revealed that vorinostat affected the alternative splicing of <i>BIM</i> mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in <i>EGFR</i>-mutated NSCLC cells homozygous for the <i>BIM</i> deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired <i>EGFR</i>-T790M mutations.</p><p><b>Conclusions:</b> These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating <i>EGFR</i>-mutated lung cancers carrying the <i>BIM</i> deletion polymorphism. <i>Clin Cancer Res; 23(12); 3139–49. ©2016 AACR</i>.</p></div>" @default.
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- W4361952115 date "2023-03-31" @default.
- W4361952115 modified "2023-09-26" @default.
- W4361952115 title "Data from Histone Deacetylase 3 Inhibition Overcomes <i>BIM</i> Deletion Polymorphism–Mediated Osimertinib Resistance in <i>EGFR-</i>Mutant Lung Cancer" @default.
- W4361952115 doi "https://doi.org/10.1158/1078-0432.c.6525318.v1" @default.
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