Discerning the role of CDK10 in driving aggressiveness and disparities of triple negative breast cancer

About This Grant

PROJECT SUMMARY Triple Negative Breast Cancer (TNBC) is the most aggressive form of breast cancer. It disproportionately impacts young and African American/Black women, who are 23% more likely to die from TNBC than their European American/White counterparts. Due to its lack of estrogen (ER) and progesterone receptors as well as HER2, TNBC is primarily treated with cytotoxic chemotherapy along with immunotherapy or antibody-drug conjugates. While effective, patients frequently experience relapse. Hence it is imperative to discover new therapies that are effective, and have limited toxicity to improve patient outcomes. This project focuses on this unmet need by discovering a new driver of TNBC that could be therapeutically targeted. By evaluating a large, publicly available dataset, we discovered that CDK10 (cyclin dependent kinase 10) is more highly expressed in TNBCs from Black compared to White patients. Elevated CDK10 is also associated with worse patient outcomes from this disease, suggesting that it may fuel disease aggressiveness. We further found that targeted disruption of CDK10 decreases TNBC cell growth and increases the incidence of aberrant mitoses and chromosomal instability. Unlike many other CDKs, loss of CDK10 in non-transformed cells has no impact on growth. This suggests that it has a high degree of selectivity for controlling tumor versus normal cells. Together, these data suggest that CDK10 may be an innovative target for therapeutic development that would result in limited toxicity. CDK10 is a “dark” kinase, meaning it is understudied with unclear functions. As a member of the cyclin dependent kinase family, it controls cell cycle progression. Inhibitors of other CDKs have been previously developed, with the most notable being those that target CDK4/6. These drugs have been practice-changing for another type of breast cancer but are generally ineffective in TNBC. This proposal will test the overarching hypothesis that suppressing CDK10 will provide a novel avenue for blocking the cell cycle and treating TNBC, using a robust set of in vitro and in vivo models. Moreover, it will discover mechanisms that control CDK10 as well as reveal how it stimulates mitosis and TNBC cell growth. This work will provide fundamental insights regarding a potential architect of TNBC aggressiveness that may serve as an effective target for treating this disease and reducing disparities in breast cancer outcomes.