Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/53719
Title: Functional Effects of a Novel BIM Deletion Polymorphism in Mediating Resistance to Tyrosine Kinase Inhibitors in Cancer
Authors: JUAN WEN CHUN
Keywords: Cancer, alternative splicing, resistance, tyrosine kinase inhibitors
Issue Date: 25-Nov-2013
Source: JUAN WEN CHUN (2013-11-25). Functional Effects of a Novel BIM Deletion Polymorphism in Mediating Resistance to Tyrosine Kinase Inhibitors in Cancer. ScholarBank@NUS Repository.
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.
URI: http://scholarbank.nus.edu.sg/handle/10635/53719
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