CDK12 is a Context-Specific Tumorigenesis Regulator and Novel Therapeutic Target in Castration-Resistant Prostate Cancer
Abstract
Prostate cancer is the most commonly diagnosed malignancy and second-leading cause of cancer death in American men. While most prostate cancers are slow-growing and treatable, a subset can metastasize to distant organs. Resistant even to deprivation of growth-promoting estosterone (hence called metastatic castration-resistant prostate cancer, or mCRPC), this form of the disease is incurable and rapidly fatal. Unfortunately, current therapies only extend the lifespan of patients with mCRPC by a few months. As such, new treatment approaches—ideally ones that address specific mutations driving tumor development and growth—are urgently needed. mCRPC tumors each contain a wide array of mutations. Indeed, it is disease heterogeneity that has largely hampered treatment efforts. Our group mapped the mutational signatures of mCRPC samples from 360 patients by whole-genome DNA sequencing. This demonstrated that mCRPC tumors are very different from one another—each containing a unique set of mutations. One mutation that had previously been described in mCRPC—inactivation of the PTEN gene, which increases cell proliferation—was common, impacting 43% of tumors analyzed. The study also identified a mutation not previously characterized in mCRPC: inactivation of the CDK12 gene. This gene encodes CDK12 protein, which functions as a key player in DNA damage responses and maintaining the integrity of the genome. While CDK12 was mutated in 7% of all samples, it was not mutated in the many tumors bearing PTEN inactivation. This is unlikely a chance phenomenon and, in fact, suggests that tumor cells with inactive PTEN actually need functional CDK12 to survive. Why is this the case? The answer might be a concept called “synthetic lethality.” When two genes have a synthetic lethal relationship, a cell can tolerate a mutation to one or the other; however, if both mutations occur, the cell dies. Synthetic lethal relationships can even exist between two cancer-related genes. If mutated individually, these genes might promote cancer, but if mutated simultaneously, cell death follows. Synthetic lethality can be leveraged for cancer treatment. To do this, one can develop an inhibitor to the protein product of one of the two genes in the synthetic lethal relationship and then use this agent to treat cancers bearing the other mutation. Here, we propose that (1) CDK12 has a synthetic lethal relationship with PTEN. Therefore, (2) chemically inhibiting CDK12 protein should impair growth of mCRPC driven by PTEN inactivation. In preliminary experiments, we specifically deleted the Cdk12 gene in prostate cells of normal mice. This yielded small precancerous lesions as mice aged. We repeated the experiment in mice that lack functional prostatic Pten and ordinarily develop large prostate tumors. Strikingly, deletion of the Cdk12 gene in these animals caused reduced tumor growth. We next evaluated a chemical inhibitor that blocks function of the CDK12 protein. Applying this inhibitor to mCRPC cells with PTEN inactivation impaired their ability to form large tumors in mice. Conversely, the inhibitor did not have this effect on mCRPC cells that lacked these common mutations. In this proposal, we will (1) conduct a detailed characterization of prostate tumors in normal and Pten knockout mice lacking functional Cdk12. We will also delete the Cdk12 gene in another mouse strain with normal Pten to verify a true synthetic lethal effect. (2) We will next conduct detailed testing of the effect of CDK12 inhibition on human mCRPC cell lines with and without mutant PTEN, both in culture and after implantation into mice. (3) Finally, we will implant patient tumor samples with and without mutant PTEN into mice and determine the ability of the CDK12 inhibitor to limit their growth. In all, this proposal explores an exciting new method to leverage synthetic lethality for the treatment of mCRPC. Our proposal contributes to two of the FY20 P
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110458
Entities
People
- Jean Tien
Organizations
- United States Army
- University of Michigan