Harnessing CDK12 Inhibition for the Treatment of HER2+ Brain Metastatic Breast Cancers
Abstract
Rationale and objectives of the proposed study: Breast cancer is the most commonly occurring cancer in women worldwide, with over 2.3 million new cases diagnosed in 2020. It is also one of the leading causes of cancer-related death among female active-duty military members, retired military personnel, and their dependents. Disease metastasis is the main cause of breast cancer mortality where disseminated tumor cells establish at distant sites and eventually compromise the function of major organs. This is especially true for breast cancer metastases to the brain, which are challenging to treat and currently remain incurable. Moreover, metastatic cells have an increased tendency to relapse and develop resistance to the anti-cancer action of current treatments. Accordingly, while substantial advances have been made in the discovery of new drugs for treating breast cancer, no approved drugs exist that selectively target the cellular mechanisms by which breast cancer cells break away from the initial tumor and colonize the brain. Therefore, there is an urgent need to develop new classes of cancer therapeutics targeting the cellular processes that drive metastasis and establishment of brain cancers, while maintaining minimal general toxicity and unwanted side-effects. The establishment of disseminated breast cancer cells in the brain involves the complex interplay between breast tumor cells and the brain microenvironment. This interplay rewires transcription patterns and tumor-promoting signaling pathways necessary for the metastatic colonization of the brain. The main objectives of our studies seek to identify targets that promote brain-specific rewiring and to develop new therapeutics that render this rewiring an exploitable vulnerability. Dysregulation of the cell cycle (process that duplicates a cell) and addiction to transcription (process that generates RNA) are hallmarks of human cancer. Enzymes involved in regulating both the cell cycle and transcription are a family of twenty kinases known as cyclin-dependent kinases (CDK). Our multi-PI research team recently reported that targeting CDK12 and 13 has potent anti-breast cancer activity (Quereda et al, 2019). CDK12/13 play key roles in transcription and our new findings support the premise that CDK12 is an important contributor to breast cancer colonization of the brain, to chemotherapy resistance mechanisms, and that CDK12 is an attractive target in brain metastatic breast cancers (BMBCs). Importantly, we have generated potent, highly selective small molecule CDK12/13 inhibitors. Our recent studies reveal that our compounds have the added unique properties of a molecular glue degrader – a new weapon to target undruggable cancer drivers. As their name suggests, this class of compounds brings proteins (that may not normally interact) together with the components of the cellular waste disposal system, leading to the subsequent degradation of the interacting protein. Importantly, if the interacting protein also controls cancer growth and spread, tagging these cancer drivers for destruction would have potent antitumor activity. Notably, our lead compound, SR-4835, not only inhibits CDK12 and CDK13 kinase activity but, through recruitment of the degradation machinery, tags certain cancer driver proteins within CDK12 and CDK13 complexes for destruction. Our studies also demonstrate that chemical alteration of SR-4835 can lead to gain or loss of glue properties, enabling strategies for the rational design of molecular glue degraders that have thus far only been discovered serendipitously. Collectively, our findings support the hypotheses that targeting CDK12/13 with molecular glue degraders will reveal new insight into CDK12/13 biology, signaling interactions that contribute to HER2+ breast cancer colonization of the brain, and will provide an important new treatment option for patients with HER2+ brain cancers. Applicability of the proposed res
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210026
Entities
People
- Andrii Monastyrskyi
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army