Background: Age-adjusted incidence and mortality rates for prostate cancer (PCa) among African Americans (AAs) are greater than among whites. The more aggressive characteristics of PCa in AAs contribute to the disparity, in addition to social determinants of health. Prior work has shown race-related differential RNA splicing of PI3Kd in PCa tissue and a novel short RNA splice variant of PI3Kd enriched in PCa from AAs. This variant drives PCa aggressiveness and associates with poorer survival for PCa. PCa cells engineered to overexpress the PI3Kd variant enriched in PCa from AAs are resistant to CAL-101, a PI3Kd inhibitor, and those overexpressing the PI3Kd variant enriched in PCa from whites are sensitive to CAL-101. Available inhibitors that target race-related RNA splicing dysregulated pathways in PCa represent potential novel therapeutic strategies for aggressive PCa.
Methods: We identified a panel of PI3Kd inhibitors of varying subunit specificity, which are available and/or currently being tested in other diseases. A panel of non-engineered PCa cell lines derived from AAs or whites were treated with the inhibitors and resulting alterations in proliferation were assessed using an Incucyte Live-Cell Imaging System. The cell lines were tested for baseline RNA and protein levels of total PI3K and levels of each PI3K subunit. After treatment, cells were tested for RNA levels of targets in pathways that cross talk with the PI3K pathway and downstream targets of PI3K signaling.
Results: The seven non-engineered PCa cell lines derived from AAs or whites varied in PI3Kd subunit expression across a 60-fold range. A panel of seven PI3Kd inhibitors varied in subunit specificity for PI3Kd, with PI3Kg (lowly expressed) being the most common secondary target. Specificity for all other subunits ranged from 5-19,000x relative to PI3Kd IC50. LNCaP and LN95 cell lines had the highest baseline expression of PI3Kd and the largest inhibition of proliferation in response to the highly PI3Kd-specific inhibitors, parsaclisib and idelalisib, whereas 22RV1, MDA PCa 2b and VCaP cell lines had the lowest baseline expression of PI3Kd and the smallest response to the highly PI3Kd-specific inhibitors. However, none of the cell lines exhibited sensitivity to umbralisib, a highly PI3Kd-specific inhibitor, suggesting that subunit baseline expression is not the only factor determining sensitivity. All cell lines exhibited marked proliferation inhibition in response to copanlisib and LY3023414, which have less subunit specificity and/or known off-target effects. Further studies of effects of these inhibitors on oncogenic signaling and PCa cell biology are underway, including evaluation of inhibitor activity in PCa patient-derived xenografts derived from AAs or whites.
Conclusions: PI3Kd inhibitors have a potential therapeutic role in PCa dependent on the PI3K subunit status of the tumor. PI3Kd inhibition has potential as a novel therapeutic strategy to improve outcomes for men with PCa driven by this mechanism.
Citation Format: Bonnie L LaCroix, Daniel J George, Jennifer A Freedman, Steven R Patierno. Race-related RNA splicing dysregulation of PI3Kd signaling: A therapeutic target for aggressive prostate cancer [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 D064.