SYNTHETIC LETHALITY OF CDK INHIBITION AND DOXORUBICIN IN TRIPLE-NEGATIVE BREAST CANCER REQUIRES P53 INACTIVATION
Date of Graduation
Doctor of Philosophy (PhD)
Robet C. Bast
Triple-negative breast cancer (TNBC) is an aggressive malignancy in which the tumors lack expression of estrogen receptor, progesterone receptor and HER2. As such, TNBC patients cannot benefit from clinically available targeted therapies and must rely on chemotherapy and surgery for treatment. While initially responding well to chemotherapy, TNBC patients are at increased risk of developing distant metastasis and have decreased overall survival compared to non-TNBC patients. A majority of TNBC tumors carry p53 mutations, enabling them to bypass the G1 checkpoint and complete the cell cycle even in the presence of DNA damage. Therefore, we hypothesized that TNBC cells are sensitive to cell cycle targeted combination therapy, which leaves non-transformed cells unharmed. Our findings demonstrate that sequential administration of the pan-CDK inhibitor roscovitine prior to doxorubicin treatment is synthetic lethal explicitly in TNBC cells. Furthermore, this novel combination therapy is well tolerated and efficacious, significantly reducing tumor volume and increasing overall survival compared to single drug treatment arms in a pre-clinical model system. Mechanistic studies found that combination treatment arrested TNBC cells in the G2/M cell cycle phase, where cells rely on homologous recombination for repair of DNA double strand breaks. Notably, combination treatment increased DNA double strand breaks, while simultaneously reducing recruitment of homologous recombination proteins. Examination of isogenic immortalized human mammary epithelial cells and isogenic tumor cell lines found that abolishment of the p53 pathway is required for combination-induced cytotoxicity; making mutated p53 a putative predictor of response to therapy. Consequently, p53 wildtype non-transformed cells are able to avoid cell death by arresting in G1. By exploiting the specific biological and molecular characteristics of TNBC tumors, this innovative therapy has the potential to greatly impact the treatment and care of TNBC patients.
triple-negataive breast cancer, combination therapy, CDK inhibitors, doxorubicin, p53, DNA damage