Therapeutic targeting of casein kinase 1? in breast cancer.

ABSTRACT: Identification of specific drivers of human cancer is required to instruct the development of targeted therapeutics. We demonstrate that CSNK1D is amplified and/or overexpressed in human breast tumors and that casein kinase 1? (CK1?) is a vulnerability of human breast cancer subtypes overexpressing this kinase. Specifically, selective knockdown of CK1?, or treatment with a highly selective and potent CK1? inhibitor, triggers apoptosis of CK1?-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 human epidermal growth factor receptor 2-positive (HER2(+)) breast cancer models. We also show that Wnt/?-catenin signaling is a hallmark of human tumors overexpressing CK1?, that disabling CK1? blocks nuclear accumulation of ?-catenin and T cell factor transcriptional activity, and that constitutively active ?-catenin overrides the effects of inhibition or silencing of CK1?. Thus, CK1? inhibition represents a promising strategy for targeted treatment in human breast cancer with Wnt/?-catenin involvement.

SUBMITTER: Rosenberg LH 

PROVIDER: S-EPMC4809734 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature