Differential Splicing of Oncogenes and Tumor Suppressor Genes in African- and Caucasian-American Populations: Contributing Factor in Prostate Cancer Disparities
Technical Report,30 Sep 2015,29 Sep 2016
George Washington University School of Medicine Washington United States
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The overarching goal of this grant award is to characterize differential splicing of oncongenes and tumor suppressor genes in prostate cancer disparities between African American AA and Caucasian American CA prostate cancer PCa. In years 1-2, we described the molecular cloning of a novel phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit PIK3CD mRNA variant that expressed in AA PCa specimens. This AA-enriched variant is referred to as the short variant of PIK3CD PIK3CD-S, which is missing exon 20 due to an exon skipping event. We demonstrated that the PIK3CD-S variant i encodes a more aggressive oncogenic signaling protein as defined by in vitro assays and mouse xenograft studies, ii is associated with worse prognosis in patients, and iii Is resistant to small molecule inhibitor idelalisib or CAL-101 selective PI3KC inhibitor FDA approved for treating hematologic cancers.Our discovery portends a genetic screening test for patients with aggressive tumors that are resistant to idelalisib therapy. In year 3 of this award, we have focused our efforts on characterizing the molecular mechanism underlying increased oncogenic signaling by PI3KC-Scompared to PI3KC-L expressed in CA PCa. Our findings demonstrate that PI3KC-L preferentially complexed with the regulatory submit p85, leading to decreased kinase activity compared to PI3KC-S that has lower affinity for p85. PI3KC-L, in the absence ofp85, exhibited kinase activity comparable to PI3KC-S but was still sensitive to the inhibitory effects of idelalisib.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research