Conclusions
Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.
Purpose
Abiraterone acetate (AA), an inhibitor of cytochrome P450 17alpha-hydroxylase/17, 20 lyase, is an FDA-approved drug for advanced prostate cancer. However, not all patients respond to AA, and AA resistance ultimately develops in patients who initially respond. We aimed to identify AA resistance mechanisms in prostate cancer cells. Experimental design: We established several AA-resistant cell lines and performed a comprehensive study on mechanisms involved in AA resistance development. RNA sequencing and phospho-kinase array screenings were performed to discover that the cAMP-response element CRE binding protein 1 (CREB1) was a critical molecule in AA resistance development.
Results
The drug-resistant cell lines are phenotypically stable without drug selection, and exhibit permanent global gene expression changes. The phosphorylated CREB1 (pCREB1) is increased in AA-resistant cell lines and is critical in controlling global gene expression. Upregulation of pCREB1 desensitized prostate cancer cells to AA, while blocking CREB1 phosphorylation resensitized AA-resistant cells to AA. AA treatment increases intracellular cyclic AMP (cAMP) levels, induces kinases activity, and leads to the phosphorylation of CREB1, which may subsequently augment the essential role of the CBP/p300 complex in AA-resistant cells because AA-resistant cells exhibit a relatively higher sensitivity to CBP/p300 inhibitors. Further pharmacokinetics studies demonstrated that AA significantly synergizes with CBP/p300 inhibitors in limiting the growth of prostate cancer cells. Conclusions: Our studies suggest that AA treatment upregulates pCREB1, which enhances CBP/p300 activity, leading to global gene expression alterations, subsequently resulting in drug resistance development. Combining AA with therapies targeting resistance mechanisms may provide a more effective treatment strategy.