Jenny Guan
Pronouns: she/her/hers
Research Mentor(s): Jean Tien
Co-Presenter:
Research Mentor School/College/Department: Pathology – MCTP / Medicine
Presentation Date: April 20
Presentation Type: Poster
Session: Session 5 – 3:40pm – 4:30 pm
Room: League Ballroom
Authors: Jenny Guan, Yunhui Cheng, Rahul Mannan, Andrew Goodrum, Shuqin Li, Jenny Choi, Jean Tien, Arul Chinnaiyan
Presenter: 41
Abstract
Background: Prostate cancer is the second leading cause of cancerous death among American men; and metastatic castration-resistant prostate cancer (mCRPC) accounts for virtually all mortality. Integrative genomic sequencing performed by our group found inactivating mutations of Cyclin Dependent Kinase 12 (CDK12) in ~7% of 360 mCRPC samples. CDK12 inactivation was associated with a genomic instability pattern characterized by focal tandem duplications. Notably, CDK12 loss defined a novel mCRPC subtype, mutually exclusive with other common cancer-related mutations — including inactivation of the tumor gene suppressor PTEN. Since CDK12 and PTEN inactivation were rarely observed in the same tumor samples, we hypothesized these genes shared a synthetic essential relationship —- i.e. while inactivation of one might promote cancer growth, simultaneous inactivation of both would impair it. Methods: We tested the hypothesis using genetically engineered mice with prostate-specific PTEN loss. This is an established model of prostate cancer in which animals develop large prostate tumors during the first 6 months of life. We ablated one or both copies of the CDK12 gene in prostate of these PTEN knockout mice to yield the following groups: (1) PTEN-/-; CDK12 +/+, (2) PTEN-/-; CDK12+/-, (3) PTEN-/-; CDK12-/-. We analyzed tumor size and histology at 16 and 24 weeks of age, and evaluated animal survival. Results: Prostates of PTEN-/-; CDK12-/- mice were smaller than those of PTEN-/-; CDK12+/+ mice and PTEN-/-; CDK12+/-mice, particularly at the 24-week time point. The proportion of aggressive adenocarcinoma in tumor samples also declined with biallelic CDK12 knockout. Finally, PTEN-/-; CDK12-/- mice showed improved survival over the other genotypes. Conclusion: CDK12 ablation blunts the growth and progression of murine prostate tumors driven by PTEN loss. This supports a synthetic essential relationship between the genes and suggests that, while CDK12 loss might promote tumor formation in some contexts, CDK12 inhibition might actually be a viable therapeutic strategy in tumors marked by PTEN inactivation.
Biomedical Sciences, Interdisciplinary
