Abstract D118: Insulin receptor splicing regulation as a potential target for improved prostate cancer disparity outcomes (2020)

Abstract Prostate Cancer is the third most commonly diagnosed cancer in the US, with 174,650 new cases predicted in 2019. Rates of incidence and mortality are 2 to 3 times higher among men from African American (AA) descent. These statistics necessitate unconventional and out-of-the box treatment approach to impede this cancer, specifically in AA men that are most likely to succumb to the cancer. Alternative splicing (AS) is a process in which a pre-mRNA can be processed into different mature mRNAs with the aid of the splice regulatory machinery. AS contributes to structural transcript variation and proteome diversity and is tightly regulated during development and differentiation. It has been shown that deregulated splicing can give rise to protein isoforms that contribute to tumor initiation, progression and resistance to therapy. The insulin receptor gene (INSR) has uniquely evolved to undergo AS to produce two isoforms: the full-length INR-B and exon 11 skipped INR-A isoform. INR-B primarily mediates the metabolic effects of insulin, whereas INR-A triggers growth-promoting effects. This increased INR-A expression promotes the proliferation of the cells because it encodes for a receptor which has high affinity for both insulin and IGF2 growth hormones and it exploits the IGF pathway to accelerate the onset of tumor-cell hallmarks like proliferation and angiogenesis. Published work as well as preliminary data from our own lab suggest that there is a significantly increased expression of INR-A levels in prostate cancer. This atypical increased expression was further confirmed in multiple prostate cancer cell-lines. Our data further shows that this conversion of INR-B to INR-A takes place in the presence of stress conditions such as hypoxia. Furthermore, the INSR expression and splicing is particularly relevant in prostate cancer since Hif1a has been shown to be significantly elevated and associated with worse prognosis in prostate cancer. Hypoxic signaling has also been found to be a key driver of malignancy as well a reason for treatment failure. Strikingly, the INR-A isoform is expressed more often in prostate cancer samples from AA males than those from European descent (EA). Our goal is to understand the role of AS in cancer and to target the splicing pathway as a therapeutic intervention. To this end, we used a novel hypoxia-induced splicing system that recapitulates the IN-R splicing seen in tumors to identify splice regulatory proteins and their respective binding sites capable of regulating INSR splicing in prostate cancer. In collaboration with Ionis Pharmaceuticals we have shown that splice-switching oligonucleotides (SSOs) can target the splicing enhancer and repressor sequences we identified to interfere with INSR splicing and cancer cell behavior. We hypothesize that decreasing the expression of the A variant will lead to decreased tumor growth and increased susceptibility to current treatment regimens that will be particularly beneficial to AA men that express high levels of the INR-A isoform. Citation Format: Safiya Khurshid, Matias Montes, Frank Rigo, Dawn S Chandler. Insulin receptor splicing regulation as a potential target for improved prostate cancer disparity outcomes [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D118.