Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

Abstract

Casein kinase 1δ/ε (CK1δ/ε) is a key component of noncanonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study, we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions (chemotaxis, invasion and communication with stromal cells) in primary CLL cells in all major subtypes of CLL. In the mouse models, CK1 inhibition slows down accumulation of leukemic cells in the peripheral blood and spleen and prevents onset of anemia. As a consequence, PF-670462 treatment results in a significantly longer overall survival. Importantly, CK1 inhibition has synergistic effects to the B-cell receptor (BCR) inhibitors such as ibrutinib in vitro and significantly improves ibrutinib effects in vivo. Mice treated with a combination of PF-670462 and ibrutinib show the slowest progression of disease and survive significantly longer compared with ibrutinib-only treatment when the therapy is discontinued. In summary, this preclinical testing of CK1δ/ε inhibitor PF-670462 demonstrates that CK1 may serve as a novel therapeutic target in CLL, acting in synergy with BCR inhibitors. Our work provides evidence that targeting CK1 can represent an alternative or addition to the therapeutic strategies based on BCR signaling and antiapoptotic signaling (BCL-2) inhibition.

Tumor promoter TPA activates Wnt/β-catenin signaling in a casein kinase 1-dependent manner

“…A very recent study demonstrated that CK1ε/δ is a novel therapeutic target in chronic lymphocytic leukemia (CLL). The CK1ε/δ inhibitor PF-670462 significantly blocked microenvironmental interactions of CLL cells and delayed leukemia development and progression in the Eμ-TCL1 mouse model ( 58 ). In this study, CK1ε and CK1δ have been identified as distinctive intracellular targets of tumor-promoting TPA.…”

Newly Developed CK1-Specific Inhibitors Show Specifically Stronger Effects on CK1 Mutants and Colon Cancer Cell Lines

“…However, off-target effects due to direct binding to microtubules and due to blockage of voltage-gated sodium channels can also be triggered by IC261 [9,10]. In cell culture and mouse models for chronic lymphocytic leukemia (CLL), treatment with the CK1δ-and ε-specific inhibitor PF-670462 resulted in a longer overall survival [11]. Inhibitor PF-4800567 showed increased selectivity toward CK1ε compared to CK1δ and induced remarkable anti-proliferative effects in different cell lines [12].…”

Lyn controls chemotaxis and motility of CLL cells via phosphorylation of ROR1

“…It has been shown earlier that in these malignancies the non-canonical Wnt pathway and BCR signaling can be targeted in a combinatorial manner. Namely, it has been observed in vivo in the mouse models of CLL where BTK inhibitor ibrutinib and anti-ROR1 antibody 45 or casein kinase 1 (CK1) inhibitors 46 showed synergistic effects. Similar behavior has been observed by Karvonen and colleagues in the in vitro model of MCL 15 .…”