Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia

0492501 - BFÚ 2019 RIV CZ eng J - Journal Article
Janovská, Pavlina - Verner, J. - Kohoutek, J. - Bryjova, L. - Gregorová, M. - Dzimkova, M. - Skabrahova, H. - Radaszkiewicz, T. - Ovesná, P. - Blanářová, O. - Němcová, T. - Hoferová, Zuzana - Vašíčková, K. - Smyčková, L. - Egle, A. - Pavlová, Š. - Poppova, L. - Plevová, K. - Pospíšilová, Š. - Bryja, Vítězslav
Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia.
Blood. Roč. 131, č. 11 (2018), s. 1206-1218. ISSN 0006-4971. E-ISSN 1528-0020
Institutional support: RVO:68081707
Keywords : receptor tyrosine kinase * cell polarity pathway * in-vitro
OECD category: Hematology
Impact factor: 16.601, year: 2018

Casein kinase 1 delta/epsilon (CK1 delta/epsilon) 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 CK1 delta/epsilon inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using 2 murine model systems based on the E mu-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resembles closely human CLL. We can demonstrate that the CK1 delta/epsilon 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 CK1 delta/epsilon 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.
Permanent Link: http://hdl.handle.net/11104/0286013