DTIC AD1050522: Differential splicing of oncogenes and pdf

DTIC AD1050522: Differential splicing of oncogenes and

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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 delta(PIK3CD) 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 PI3K/AKT 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

• Creator/s: Defense Technical Information Center
• Date: 12/1/2017
• Book Topics/Themes: DTIC Archive, Lee, Norman H, George Washington University School of Medicine Washington United States, prostate cancer, African Americans, biological factors, amino acids, neoplasms, cell physiological processes, peptides, therapy, proteins, health services, antineoplastic agents, gene expression, castration, resistance (biology), CAUCASIANS

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