Payal Sutaria
Pronouns: she/her
Research Mentor(s): Palak Shah
Research Mentor School/College/Department: Pathology – MCTP / Medicine
Program: UROPF
Session: Session 3 (11:00am – 11:50am)
Authors: Payal Sutaria, Ruidong Li, Palak Shah, Jean Tien, Nicolette Loeding, Alexander Koons, Xuhong Cao, Arul Chinnaiyan
Abstract
Cyclin-dependent kinase-12 (CDK12) is a transcription elongation-associated CTD kinase. Recently, a novel molecular subclass of prostate cancer has been identified, wherein 7% patients have biallelic inactivating mutations in CDK12. This loss of CDK12 is associated with genomic instability and focal tandem duplications. However, the molecular mechanisms by which loss of CDK12 affects prostate carcinogenesis is poorly understood. Using a novel mouse prostate organoid model system with CDK12 loss, we interrogated molecular mechanisms by which CDK12 loss affects prostate tumorigenesis. Using RNA sequencing, we previously found Myc signaling upregulation in CDK12 KO organoids. Previous studies have indicated an association between response to Bromodomain and extra-terminal (BET) inhibitors and Myc expression. Hence, in the current study, we aimed to determine whether CDK12 loss affects response to BET inhibitors. To achieve this goal, we used the techniques of 3D organoid cell culture, CellTiter-Glo® 3D Cell Viability Assay, Western Blotting, and qPCR. Using CellTiter-Glo® 3D Cell Viability Assay, we found that prostate CDK12 KO organoids are resistant to BET inhibitors JQ1 and OTX 015. Additionally, we confirmed that prostate CDK12 KO organoids have elevated Myc protein and RNA levels, but unchanged upstream BRD protein levels. Furthermore, prostate CDK12 KO organoids showed impaired decrease in Myc protein levels in response to JQ1 compared to WT organoids. Moreover, we found that CDK12 mediated regulation of Myc and response to JQ1 is context dependent, and inhibition of Myc reversed resistance to JQ1 for prostate CDK12 KO organoids. In summary, our findings have identified CDK12 as a novel regulator of Myc signaling and BET inhibitor response via Myc signaling in prostate epithelial cells. Our novel findings have the potential to facilitate decisions of contraindication of BET inhibitors for prostate cancer patients with CDK12 biallelic loss.
