Mechanistic Investigation of Breast Cancer Synthetic Lethality through Inhibition of CDK12
Abstract
The project addresses these Overarching Challenges: Identify what drives breast cancer growth; determine how to stop it; and revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. Research rationale: There are two main pathways that repair severe DNA damage in cells: the first pathway connects broken DNA ends by resynthesizing the missing sequence using the second copy of our genes as a template, while the second pathway simply re-joins the broken DNA ends. Mutations in genes involved in both of these pathways are frequently found in cancer cells. Recent studies show that tumors with inactivating mutations in one pathway can be effectively treated with drugs that inhibit the other pathway. After drug treatment, these tumor cells cannot survive because both repair pathways are impaired. Normal cells, on the other hand, will still retain one functional pathway to repair DNA damage after drug treatment. As a result, side effects associated with this approach are typically milder than traditional cancer therapies. Understanding the function of both repair pathways in cancer will benefit the development of new therapies. Recent evidence suggests that a protein named CDK12 is a regulator of the resynthesis pathway, and mutations in CDK12 have been found in many tumor types including breast cancer. We predict that breast tumors with defects in the re-joining pathway can be effectively treated by inhibiting CDK12 function. However, which genes and which breast cancer subtypes are amenable to this treatment approach are not known. Our preliminary results indicate that CDK12 likely regulates an essential cellular process termed "alternative splicing," where gene segments are assembled in alternative orders to create different functional versions of the same gene. We believe that one of the functional properties of CDK12 is to regulate the gene expression and/or alternative splicing of genes involved in the resynthesis pathway. The research objective is to understand how CDK12 controls the alternative splicing of genes involved in the DNA repair pathways and to determine which breast cancer types containing mutations in the DNA damage repair pathways will be killed by drugs targeting CDK12. Aim 1 will identify which genes undergo alternative splicing by CDK12 in response to DNA damage. Aim 2 will determine how CDK12 controls gene expression. Aim 3 will determine how CDK12 controls alternative splicing. Aim 4 will identify which DNA damage repair gene mutations found in breast cancer tumor cell lines and patient derived tumors will be killed by drug candidates targeting CDK12. The beneficial clinical applications of our research will be a new treatment strategy for breast cancer patients. Current strategies targeting DNA repair processes only apply to patients with defects in the resynthesis pathway. If successful, our research will open this therapeutic approach to breast cancer patients with defects in the re-joining pathway, greatly extending the types of patients who can benefit. A benefit of this treatment strategy is that it is predicted to have fewer side effects and may be less susceptible to the development of drug resistance that often occurs with standard therapies. The proposed research is still early in the expected development time for new drug therapies, which typically take 10-15 years before clinical application. The interim outcomes of our research will validate CDK12 as a target in this new treatment approach, and due to our collaboration with a pharmaceutical company, we have proof-of-concept drug-like molecules that can accelerate the validation process in preclinical tumor models. The ultimate impact of our research towards ending breast cancer could be a new drug treatment strategy with reduced side effects and improved efficacy that may eliminate breast tumors from patients after they are detected.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610023
Entities
People
- Gregg Morin
Organizations
- BC Cancer Agency
- United States Army