Targeting HUNK: Pharmacological Insights and Therapeutic Implications

Abstract ID 90902 Poster Board 046 Ultimately treatment resistance and metastasis are what kill individuals living with breast cancer. Identifying novel, effective treatments to address this issue is of critical importance. Hormonally Upregulated Neu-associated Kinase (HUNK) is an emerging target for HER2-positive (HER2+) and triple negative (TNBC) breast cancers. To date, a selective HUNK inhibitor has not been developed. Significant evidence has demonstrated that inhibiting HUNK using a variety of HER2/neu-positive (HER2/neu+) BC models, including those that are resistant, inhibits tumorigenesis. Evidence shows that targeting HUNK's activity through shRNA downregulation in human HER2+ BC cells, genetic deletion (Hunk-/-) in the MMTV-neu mouse model, or by inhibition of kinase activity using a kinase deficient HUNK mutant (K91M) results in impaired tumorigenesis even in the face of resistance. Additional evidence in TNBC models shows that HUNK downregulation or inhibition results in a decrease in tumor cell migration, and invasion. Targeting of HUNK in 4T1 cells that are orthotopically implanted into the mouse mammary gland inhibits metastasis. Taken together, the above findings implicate HUNK as a target in certain aggressive subtypes of breast cancer, HER2+ and TNBC, and prompted further investigation into the merits of identifying a chemical inhibitor of HUNK. Here, we report on a newly characterized HUNK inhibitor. Evidence will be provided to demonstrate compound selectivity, efficacy, and potency in vitro using breast cancer cell lines and in vivo using orthotopic mammary tumor and metastasis models. Data indicates that this inhibitor is selective and has efficacy in HER2+ and TNBC breast cancer models. This study was supported by R01CA187305, R01CA269508, and awards from 100 Voices of Hope and a Research Support Funds Grant from IUPUI to E.S.Y.