Tuesday, April 30, 2024
4/30/2024
PROJECT SUMMARY/ABSTRACT Triple Negative Breast Cancer (TNBC) is a highly aggressive disease subtype that conveys poor patient outcomes. While targeted therapies exist and are highly effective for other breast cancer subtypes, there is a paucity of targets/targeted agents for this disease, making cytotoxic chemotherapy the standard of care. Identifying approaches that could sensitize TNBC to targeted therapies that are effective in other breast cancer subtypes or in small populations of TNBC, should provide a accelerated approach for expanding the inventory of treatments for this disease. This proposal focuses on leveraging inhibitors of NEK2, a mitotic kinase that is overexpressed in TNBC, to potentiate the efficacy of two FDA-approved drug classes: CDK4/6 inhibitors and PARP inhibitors. Unlike other breast cancers, TNBC are generally resistant to CDK4/6 inhibitors. In contrast, PARP inhibitors are effective in TNBC, but in the limited number of cancers that have mutations in the BRCA1 gene. The efficacy of both can be improved in various model systems by elevating chromosomal instability (CIN) and decreasing EMT (epithelial to mesenchymal transition). Notably, mitotic kinases, including NEK2, can control both of these phenotypes, suggesting that they may be strong targets for improving CDK4/6 and PARP inhibitor efficacy, but this has not yet been explored. Mitotic kinases were thought to be ideal cancer drug targets because their disruption leads to mitotic delay and dysfunction, ultimately inducing CIN that results in cell death or senescence. However, drugs targeting these enzymes have often failed in clinical trials due to dose-limiting toxicities as a result of their essentiality in normal cells. Identifying and leveraging novel mitotic kinases that are more selective for tumor versus normal cells should greatly improve the ability to sensitize TNBC to CDK4/6 and PARP inhibitors. NEK2 stands out as a potential target because it is overexpressed in triple negative breast cancers (TNBC) and is associated with worse disease outcomes. Therapeutically targeting NEK2 can also potentiate the efficacy of taxanes, a standard-of-care drug for this disease, without inducing toxicity in mice. Most importantly and unlike other mitotic kinases, the growth inhibition resulting from blocking NEK2 is selective for TNBC and not normal cells. Together, these results suggest that targeting NEK2 may provide a novel approach for improving CDK4/6 and PARP inhibitor response in TNBC without increasing toxicity. In Specific Aim 1, we will expand our preliminary data demonstrating proof-of-principle that NEK2 inhibitors can potentiate CDK4/6 inhibitor response in a murine xenograft model to assess the impact of NEK2 inhibition on the efficacy of these drugs using several in vitro and in vivo models of TNBC that reflect the genomic heterogeneity of this disease. In Specific Aim 2 we will determine if the ability of targeting NEK2 to increase the efficacy of CDK4/6 and/or PARP inhibitors involves modulation of CIN, EMT, or new, as yet undiscovered pathways. Together, these studies will provide the foundation for developing clinically useful NEK2 inhibitors and pairing them with CDK4/6 and PARP inhibitors to treat TNBC patients.
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