Therapeutic targeting of casein kinase 1δ in breast cancer

Abstract

Identification of specific drivers of human cancer is required to instruct the development of targeted therapeutics. Here we demonstrate that CSNK1D is amplified and/or overexpressed in human breast tumors and that CK1δ is a vulnerability of human breast cancer subtypes overexpressing this kinase. Specifically, selective knockdown of CK1δ, or treatment with a highly selective and potent CK1δ inhibitor, triggers apoptosis of CK1δ-expressing breast tumor cells ex vivo, tumor regression in orthotopic models of triple negative breast cancer, including patient-derived xenografts, and tumor growth inhibition in HER2+ breast cancer models. We also show that Wnt/β-catenin signaling is a hallmark of human tumors overexpressing CK1δ, that disabling CK1δ blocks nuclear accumulation of β-catenin and T cell factor transcriptional activity, and that constitutively active β-catenin overrides the effects of inhibition or silencing of CK1δ. Thus, CK1δ inhibition represents a promising strategy for targeted treatment in human breast cancer with Wnt/β-catenin involvement.

Development of dual casein kinase 1δ/1ε (CK1δ/ε) inhibitors for treatment of breast cancer

“…25–26 Mechanistic studies are consistent with the premise that CK1δ controls breast cancer tumorigenesis via its effect on β-catenin, which plays known roles as an effector of aberrant Wnt signaling in human breast cancer. 26 …”

“…Recent discoveries from our laboratories establish casein kinase 1 delta (CK1δ) as an essential regulator of β-catenin activity that is overexpressed and amplified in human breast cancer. 16 …”

“…3a, 20b Nonetheless, available data clearly shows that targeted inhibition of CK1δ/CK1ε is a viable, highly attractive anticancer strategy yet to be fully developed. 26 …”

“…25 These agents induce proliferative arrest and rapid apoptosis of CK1δ/CK1ε-expressing human luminal B, HER2+ and triple negative cancer cells ex vivo and SR-3029 induces tumor regression in orthotopic xenograft models in vivo. 26 Specifically, genetic knockdown or pharmacological inhibition of CK1δ using SR-3029 blocks β-catenin nuclear localization and TCF transcriptional activity, induces rapid apoptosis and provokes tumor regression in patient derived orthotopic models of triple negative breast cancer. 25–26 Mechanistic studies are consistent with the premise that CK1δ controls breast cancer tumorigenesis via its effect on β-catenin, which plays known roles as an effector of aberrant Wnt signaling in human breast cancer.…”

CK1δ: an exploitable vulnerability in breast cancer

“…Cheong and Virshup, who succinctly summarize and highlight the advances of our original manuscript (1). In addition to stressing the potential translational importance of our studies, Drs.…”