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bioRxiv · 10.1101/2024.10.01.616176

CYP3A5 inhibition causes G1/S blockade and synergizes with CDK4/6 inhibitor to suppress prostate cancer cell growth: Implications in reducing health disparity

Sharma, J.·Mohammed, I. K.·Tillett, R. L.·McLean, J.·Shen, S.·Singh, A. P.·Goodman J., O. B.·Oh, E. C.·Mitra, R.
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Abstract

Prostate cancer (PC) is a leading cause of death in men because of the high incidence and long-term inefficacy of the existing treatment options. Furthermore, it exhibits significant health disparities that affect African-American (AA) men more adversely than others do. Previously, we established CYP3A5, a highly expressed protein in AAs PC, as a positive regulator of androgen receptor (AR) signaling. We examined the impact of CYP3A5 depletion on genome-wide transcriptional output using RNA sequencing to gain deeper mechanistic insights. The data revealed that 561 genes were downregulated and 263 were upregulated upon silencing of CYP3A5 in PC cells. Furthermore, in silico pathway analyses of differentially expressed genes suggested that the cell cycle regulation pathway was most significantly affected by CYP3A5 inhibition. Cell cycle analysis of CYP3A5-silenced cells and those treated with clobetasol, a specific CYP3A5 pharmacological inhibitor, showed G1/S phase blockade. Both CYP3A5-depletion and pharmacological inhibition resulted in the downregulation of cyclin D, cyclin B, and CDK2, along with the upregulation of p27kip1 but had minimal effects on CDK4/6 levels. Combination treatment with clobetasol and the CDK4/6 inhibitor palbociclib exhibited synergy with combination index (CI) values ranging from 0.28-0.78. Our findings support the utility of CYP3A5 as a druggable therapeutic target that works more effectively in combination with CDK4/6 inhibition to limit the progression of PC, especially for AA patients with AA. This combination addresses CDK4/6 inhibitor resistance, which is often linked to CDK2 overexpression, and can potentially be useful in reducing disparities in the clinical outcomes of PC. SignificanceOur study highlights CYP3A5 as a key regulator of the cell cycle in prostate cancer (PC). Its overexpression in African American (AA) patients may be a key molecular driver of disparities in outcomes. The combination of CYP3A5 and CDK4/6 inhibitors shows a synergistic effect on therapeutic outcomes and addresses CDK2-mediated resistance. Thus, targeting both CYP3A5 and CDK4/6 could improve treatment outcomes, especially in AA PC patients.

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Sharma, J., Mohammed, I. K., Tillett, R. L., McLean, J., Shen, S., Singh, A. P., Goodman J., O. B., Oh, E. C., Mitra, R.. 2024-10-03. CYP3A5 inhibition causes G1/S blockade and synergizes with CDK4/6 inhibitor to suppress prostate cancer cell growth: Implications in reducing health disparity. https://doi.org/10.1101/2024.10.01.616176

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