Differential splicing of oncogenes and tumor suppressor genes in African and Caucasian American populations: contributing factor in prostate cancer disparities
Technical Report,30 Sep 2013,29 Sep 2017
George Washington University School of Medicine Washington United States
Pagination or Media Count:
The overarching goal of this grant is to characterize differential splicing of oncogenes in African American AA versus Caucasian American CA prostate cancer PCa. We focused our efforts on two oncogenes, phosphatidylinositol-4,5-bisphosphate 3-kinase deltaPIK3CD and fibroblast growth factor receptor 3 FGFR3. We cloned novel short -S splice variants PIK3CD-S missing exon 20 due to exon skipping event and FGFR3-S missing exon 14 that are enriched in AA PCa specimens. PCa cell lines ectopically over-expressing AA-enriched PIK3CD-S exhibited enhanced activation of the PI3KAKT pathway compared to the same lines over-expressing the CA enriched long -L variant PIK3CD-L retains exon 20. Moreover, proliferative capacity of the CA-variant lines was sensitive to inhibition by CAL-101, a small molecule inhibitor designed specifically against PIK3CD. In contrast, proliferative capacity of the AA-variant lines was resistant to CAL-101 inhibition. And these findings CA variants sensitive and AA variants insensitive to CAL-101 were recapitulated in a xenograft mouse model of proliferation and metastasis. Analogously, we demonstrate that FGFR3-S i encodes a more aggressive oncogenic signaling protein compared to CA-enriched FGFR3-L retains exon 14 as defined by in vitro assays, ii is associated with worse prognosis in patients, and iii is resistant to the tyrosine kinase inhibitor dovitinib potential treatment for metastatic castrate-resistant PCa.Our discovery portends a genetic screening test for aggressive tumors that are resistant to small molecule inhibitors.
- Medicine and Medical Research