Triple negative breast cancer (TNBC) makes up about 20% of all breast cancers (BCs), and the majority of BCs associated with BRCA1 mutations. The fact that TNBCs are more aggressive with poorer prognoses and no targeted therapies places them in the forefront of cancers requiring targeted preventive and treatment pharmaceutical intervention. TNBCs exhibit a high incidence of TP53 mutations (>80%), loss of RB expression (20%) and PI3KCA mutations (7-9%). Activation of the Wnt/?-catenin pathway is common in TNBCs and the related basal-like BCs. Autocrine feed-forward stimulation by Wnt ligands may underlie this Wnt pathway hyperactivation. When Wnt is activated by its ligand, it binds to the transmembrane receptor frizzled (FZD) which, in turn, recruits Disheveled (DVL). This leads to phosphorylation of the tail of transmembrane LRP5/6 by CK1?, all of which results in disassembling of the ?-catenin destruction complex. The now stabilized ?-catenin translocates to the nucleus where it induces transcription of target genes in the Wnt pathway. The phosphorylation of LRP5/6, and probably DVL, by CK1? (and CK1?) thus plays a role in carcinogenic progression via Wnt pathway activation, but also via other pathways. Multiple attempts have been made to develop agents that inhibit serine/threonine kinases such as CK1?/?, but most exhibit disadvantages, including lack of specificity. In contrast, the dual CK1?/CK1? inhibitor SR-3029 is one of 2 compounds that do exhibit the desired specificity and it inhibits TNBC tumor growth in vitro and in vivo (human breast cancer cell lines; xenografts and patient-derived xenografts derived from TNBCs in immunosuppressed hosts). Furthermore, CK1? is overexpressed and amplified in 36% of breast cancers, regardless of intrinsic subtype. CK1? is also overexpressed in multiple breast cancer cell lines, including TNBC, HER2+ cell lines, but not ER+ cell lines. SR-3029 shows selective inhibition of in vitro and in vivo growth of cell lines that overexpress CK1?. In sum, hyperactivation of the Wnt/?-catenin pathway is a hallmark of breast tumors that overexpress CK1?, in turn making such tumors likely to be vulnerable to inhibition by SR-3029. The overall objective of this task order is to test the efficacy of SR-3029 in prevention of breast cancers that occur in association with inherited BRCA1 mutations and cancers that show hyperactivation of the Wnt pathway.
