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https://scholarbank.nus.edu.sg/handle/10635/53719
DC Field | Value | |
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dc.title | Functional Effects of a Novel BIM Deletion Polymorphism in Mediating Resistance to Tyrosine Kinase Inhibitors in Cancer | |
dc.contributor.author | JUAN WEN CHUN | |
dc.date.accessioned | 2014-05-31T18:03:11Z | |
dc.date.available | 2014-05-31T18:03:11Z | |
dc.date.issued | 2013-11-25 | |
dc.identifier.citation | 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. | |
dc.identifier.uri | http://scholarbank.nus.edu.sg/handle/10635/53719 | |
dc.description.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. | |
dc.language.iso | en | |
dc.subject | Cancer, alternative splicing, resistance, tyrosine kinase inhibitors | |
dc.type | Thesis | |
dc.contributor.department | NUS GRAD SCH FOR INTEGRATIVE SCI & ENGG | |
dc.contributor.supervisor | ONG SIN TIONG | |
dc.contributor.supervisor | AXEL HILLMER | |
dc.description.degree | Ph.D | |
dc.description.degreeconferred | DOCTOR OF PHILOSOPHY | |
dc.identifier.isiut | NOT_IN_WOS | |
Appears in Collections: | Ph.D Theses (Open) |
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Juan Wen Chun (JuanWC).pdf | 1.98 MB | Adobe PDF | OPEN | None | View/Download |
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