The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells

Maharaj, Kamira; Powers, John J.; Achille, Alex; Mediavilla-Varela, Melanie; Gamal, Wael; Burger, Karen L.; Fonseca, Renee; Jiang, Kun; Miskin, Hari P.; Maryanski, Dave; Monastyrskyi, Andrii; Duckett, Derek R.; Roush, William; Cleveland, John L.; Sahakian, Eva; Pinilla‐Ibarz, Javier

doi:10.1182/bloodadvances.2020001800

Cited by 56 publications

(71 citation statements)

References 37 publications

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“…In line with these observations, CK1ε inhibition was able to block cartilage destruction in the mouse osteoarthritis model [137]. In addition, CK1 inhibition can modulate T cells-CK1δ was shown to be essential for the formation of the immunological synapse [140] and CK1ε inhibition by umbralisib and PF-4800567 could protect Tregs and prevent immune system mediated toxicities in CLL patients treated with PI3K inhibitors [96,133].…”

Section: Summary and Future Directionsmentioning

confidence: 56%

“…Two recent studies have assessed the possible contribution of CK1ε inhibition to the clinical effects of umbralisib by comparing umbralisib to duvelisib and/or idelalisib, two approved PI3K inhibitors devoid of CK1 inhibitory activity [57,96]. In the first study, authors asked why umbralisib and not idelalisib showed specific cytotoxicity in CLL, lymphoma and myeloma cells when combined with proteasome inhibitor carfilzomib [57].…”

Section: Umbralisib a Dual Pi3kδ-ck1ε Inhibitor Demonstrates Safetymentioning

confidence: 99%

“…In the second study [96], authors analyzed the reasons for lower immune-mediated toxicity of umbralisib in comparison with other FDA-approved PI3K inhibitors. They hypothesized that CK1ε inhibition might lead to an increase of regulatory T-cell (Treg) activity, immune suppression, and thereby lower the risk of immune-mediated toxicities frequently observed with prior PI3K inhibitors.…”

Section: Umbralisib a Dual Pi3kδ-ck1ε Inhibitor Demonstrates Safetymentioning

confidence: 99%

“…Several pan-CK1 or CK1δ/ε dual inhibitors appear to be well tolerated in mouse [8,30,134] and umbralisib data suggests that CK1ε inhibition is also well tolerated in human patients [96,133]. However, CK1 kinases bear an essential role in many homeostatic processes and the redundancy of individual CK1 isoforms (mainly CK1δ and CK1ε) is common.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

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Targeting Casein Kinase 1 (CK1) in Hematological Cancers

Janovská

Normant

Miskin

et al. 2020

IJMS

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The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.

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Section: Summary and Future Directionsmentioning

confidence: 56%

Section: Umbralisib a Dual Pi3kδ-ck1ε Inhibitor Demonstrates Safetymentioning

confidence: 99%

Section: Umbralisib a Dual Pi3kδ-ck1ε Inhibitor Demonstrates Safetymentioning

confidence: 99%

Section: Summary and Future Directionsmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Casein Kinase 1 (CK1) in Hematological Cancers

Janovská

Normant

Miskin

et al. 2020

IJMS

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“…Weerdt et al reported that after 1 year of venetoclax-based therapy, frequencies of tumor-supportive T-follicular helper cells, Tregs and PD-1 + CD8 + T cells were significantly decreased in CLL patients (40). Other studies have demonstrated that inhibition or silencing of PI3Kd in preclinical CLL models modulates T-cell subsets, particularly Tregs (41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

HDAC6 Inhibition Alleviates CLL-Induced T-Cell Dysfunction and Enhances Immune Checkpoint Blockade Efficacy in the Eμ-TCL1 Model

et al. 2020

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Development of chronic lymphocytic leukemia (CLL) is associated with severe immune dysfunction. T-cell exhaustion, immune checkpoint upregulation, and increase of regulatory T cells contribute to an immunosuppressive tumor microenvironment. As a result, CLL patients are severely susceptible to infectious complications that increase morbidity and mortality. CLL B-cell survival is highly dependent upon interaction with the supportive tumor microenvironment. It has been postulated that the reversal of T-cell dysfunction in CLL may be beneficial to reduce tumor burden. Previous studies have also highlighted roles for histone deacetylase 6 (HDAC6) in regulation of immune cell phenotype and function. Here, we report for the first time that HDAC6 inhibition exerts beneficial immunomodulatory effects on CLL B cells and alleviates CLL-induced immunosuppression of CLL T cells. In the Eμ-TCL1 adoptive transfer murine model, genetic silencing or inhibition of HDAC6 reduced surface expression of programmed death-ligand 1 (PD-L1) on CLL B cells and lowered interleukin-10 (IL-10) levels. This occurred concurrently with a bolstered T-cell phenotype, demonstrated by alteration of coinhibitory molecules and activation status. Analysis of mice with similar tumor burden indicated that the majority of T-cell changes elicited by silencing or inhibition of HDAC6 in vivo are likely secondary to decrease of tumor burden and immunomodulation of CLL B cells. The data reported here suggest that CLL B cell phenotype may be altered by HDAC6-mediated hyperacetylation of the chaperone heat shock protein 90 (HSP90) and subsequent inhibition of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Based on the beneficial immunomodulatory activity of HDAC6 inhibition, we rationalized that HDAC6 inhibitors could enhance immune checkpoint blockade in CLL. Conclusively, combination treatment with ACY738 augmented the antitumor efficacy of anti-PD-1 and anti-PD-L1 monoclonal antibodies in the Eμ-TCL1 adoptive transfer murine model. These combinatorial antitumor effects coincided with an increased cytotoxic CD8+ T-cell phenotype. Taken together, these data highlight a role for HDAC inhibitors in combination with immunotherapy and provides the rationale to investigate HDAC6 inhibition together with immune checkpoint blockade for treatment of CLL patients.

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