Functional Effects of a Novel BIM Deletion Polymorphism in Mediating Resistance to Tyrosine Kinase Inhibitors in Cancer

Abstract

Resistance to tyrosine kinase inhibitors (TKIs) remain a problem in some individuals with kinase-driven cancers. Using paired-end DNA sequencing, we discovered a novel deletion polymorphism within intron 2 of the pro-apoptotic gene, BIM, that is associated with TKI-resistance. I found that the polymorphism switches BIM splicing from exon 4 to exon 3, resulting in the expression of BIM variants that lacked the apoptosis-inducing BH3 domain. Using cell lines that harbor the deletion, I observed that the deletion was sufficient to confer TKI-resistance in chronic myelogenous leukemia and EGFR-mutated non-small-cell lung cancer. Notably, this resistance can be overcome by BH3-mimetics. Analysis of the deletion revealed that there are redundant cis-elements that repress inclusion of exon 3. Furthermore, I have also identified two splicing regulators, PTBP1 and hnRNP C, that repress exon 3 inclusion. Collectively, these results provide a novel mechanism by which a polymorphism mediates TKI-resistance in targeted cancer therapy.