Protein kinase CK1-alpha may be a viable target in mantle cell lymphoma (MCL), according to research published in Frontiers in Oncology.
MCL is an aggressive subtype of non-Hodgkin lymphoma associated with frequent relapse, and is considered incurable. The disease has previously been linked with aberrant signaling pathway activity, including in the B cell-related signaling cascades.
While clinically available therapies, including ibrutinib, which targets Bruton tyrosine kinase, have previously been shown to be effective in the MCL setting, high relapse rates suggest a need for other treatments with targets involved in the B cell-related signaling cascade.
The protein kinase CK1 family of isoforms, which are encoded by several different genes, are involved in a variety of cellular processes. The alpha isoform, which is encoded by CSNK1A1, is known to modulate several signaling pathways, including those implicated in the B cell signaling cascade. For this study, researchers evaluated the role of CK1-alpha in MCL downstream of B cell receptor (BCR) signaling.
The authors isolated and cultured MCL cell lines, as well as B cells without lymphoma, from 20 patients with MCL. The majority of patients were CD5-positive and CD23-negative.
Analysis showed that CK1-alpha was more likely to be expressed on MCL cells than healthy B cells. Loss or inactivation of CK1-alpha, furthermore, led to MCL cell apoptosis and proliferation arrest. CK1-alpha was also linked with BCR signaling, including the Bruton tyrosine kinase pathway. Regulation of Bruton tyrosine kinase via a physical interaction with CK1-alpha was noted.
The authors noted, furthermore, that inhibiting CK1-alpha in combination with the use of ibrutinib or duvelisib, an inhibitor of PI3K–gamma/delta, worked synergistically and increased MCL cell cytotoxicity. Combining this mechanism with either drug decreased overall BCR signaling pathway activation.
“Our results are particularly meaningful in the perspective of developing novel strategies that abrogate BCR activation,” the authors wrote. “Therefore, [CK1-alpha] may be a key target opening new perspectives in the treatment of MCL patients, especially those with relapsed/refractory disease.”
Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Manni S, Fregnani A, Quotti Tubi L, et al. Protein kinase CK1α sustains B-cell receptor signaling in mantle cell lymphoma. Front Oncol. 2021;11:733848. doi:10.3389/fonc.2021.733848