Therapeutic targeting of casein kinase 1delta in breast cancer
Menée in vitro et in vivo, cette étude met en évidence des mécanismes suggérant l'intérêt de développer des inhibiteurs de CSNK1D pour le traitement des patientes atteintes d'un cancer du sein
Casein kinase 1δ (CK1δ) is a protein that helps regulate a variety of cellular processes and is overexpressed in a large percentage of breast and other cancers. Rosenberg et al. show that CK1δ contributes to the growth of breast tumors by activating the Wnt signaling pathway, which is carcinogenic, and that it can be inhibited by RNA interference or by a small-molecule drug. Treatment with a small-molecule inhibitor of CK1δ, called SR-3029, was effective at reducing the growth of breast cancer in multiple mouse models without any signs of major toxicity, suggesting that this therapeutic approach may be a good candidate for testing in human patients.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 1δ (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 human epidermal growth factor receptor 2–positive (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.