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Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia

Leukemia volume 28, pages 179–182 (2014)Cite this article

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Chronic lymphocytic leukemia (CLL) remains a therapeutic challenge. New immuno-chemotherapeutic approaches have had a significant impact, improving overall survival. However, not all patients can tolerate aggressive regimens, high-risk groups continue to have a poor response, and patients still relapse.1 Therefore, novel therapeutic strategies involving molecular-targeting, rationally designed treatments are particularly desirable.2

CK2 is a ubiquitous, constitutively active serine/threonine protein kinase frequently involved in cancer.3 We and others previously showed that CLL cells rely on high CK2 expression and activity for their viability,4, 5 similar to their dependence on PI3K.6 Notably, CK2 has been consistently linked to the activation of PI3K signaling pathway through its ability to phosphorylate and thereby inactivate PTEN, the main negative regulator of the pathway.4, 7

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References

  1. Gribben JG, O'Brien S . Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 2011; 29: 544–550.

    Article  Google Scholar 

  2. Faderl S, Ferrajoli A, Frankfurt O, Pettitt A . Treatment of B-cell chronic lymphocytic leukemia with nonchemotherapeutic agents: experience with single-agent and combination therapy. Leukemia 2009; 23: 457–466.

    Article  CAS  Google Scholar 

  3. Piazza F, Manni S, Ruzzene M, Pinna LA, Gurrieri C, Semenzato G . Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways. Leukemia 2012; 26: 1174–1179.

    Article  CAS  Google Scholar 

  4. Martins LR, Lucio P, Silva MC, Anderes KL, Gameiro P, Silva MG et al. Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia. Blood 2010; 116: 2724–2731.

    Article  CAS  Google Scholar 

  5. Shehata M, Schnabl S, Demirtas D, Hilgarth M, Hubmann R, Ponath E et al. Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia. Blood 2010; 116: 2513–2521.

    Article  CAS  Google Scholar 

  6. Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas JA, Sanchez A, Martin-Saavedra FM et al. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 2004; 18: 1391–1400.

    Article  CAS  Google Scholar 

  7. Barata JT . The impact of PTEN regulation by CK2 on PI3K-dependent signaling and leukemia cell survival. Adv Enzyme Regul 2011; 51: 37–49.

    Article  CAS  Google Scholar 

  8. Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O'Brien SE et al. CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 2010; 70: 10288–10298.

    Article  CAS  Google Scholar 

  9. Marschke R, Borad M, McFarland R, Alvarez R, Lim J, Padgett C et al. Findings from the Phase I clinical trials of CX-4945, an orally bioavailable inhibitor of CK2. J Clin Oncol 2011; 29 (Suppl) abstract 3087.

    Article  Google Scholar 

  10. Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F et al. Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ 2005; 12: 668–677.

    Article  CAS  Google Scholar 

  11. Ringshausen I, Oelsner M, Weick K, Bogner C, Peschel C, Decker T . Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL. Leukemia 2006; 20: 514–520.

    Article  CAS  Google Scholar 

  12. Longo PG, Laurenti L, Gobessi S, Petlickovski A, Pelosi M, Chiusolo P et al. The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease. Leukemia 2007; 21: 110–120.

    Article  CAS  Google Scholar 

  13. el Rouby S, Thomas A, Costin D, Rosenberg CR, Potmesil M, Silber R et al. p53 gene mutation in B-cell chronic lymphocytic leukemia is associated with drug resistance and is independent of MDR1/MDR3 gene expression. Blood 1993; 82: 3452–3459.

    CAS  Google Scholar 

  14. Dohner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M et al. 11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis. Blood 1997; 89: 2516–2522.

    CAS  Google Scholar 

  15. Tsimberidou AM, Keating MJ . Treatment of patients with fludarabine-refractory chronic lymphocytic leukemia: need for new treatment options. Leuk Lymphoma 2010; 51: 1188–1199.

    Article  CAS  Google Scholar 

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Acknowledgements

We are grateful to all the patients who contributed to this study. We thank Dr Riccardo Dalla-Favera for providing the MO1043 cell line and Dr John Byrd for providing the WaC3CD5 cell line. We also thank the Helena Alaìz (cytogenetics section of the Hemato-oncology lab at Instituto Português de Oncologia). This work was mainly supported by the grant PIC/IC/83193/2007 from Fundação para a Ciência e a Tecnologia; and also by Associazione Italiana per la Ricerca sul Cancro AIRC (Investigator Grant and Special Program Molecular Clinical Oncology – 5 per mille #9965), Ricerca Finalizzata 2010 – Ministero della Salute, Roma. LRM received an FCT-SFRH PhD fellowship.

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Authors and Affiliations

  1. Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal

    L R Martins, A Melão, I Antunes, B A Cardoso & J T Barata

  2. CEDOC, Faculdade de Ciências Médicas, FCM, Universidade Nova de Lisboa and Instituto Português de Oncologia, Lisbon, Portugal

    P Lúcio & M G Silva

  3. Cylene Pharmaceuticals, San Diego, CA, USA

    R Stansfield & D Drygin

  4. Istituto Scientifico San Raffaele, Milano, Italy

    M T S Bertilaccio & P Ghia

  5. Università Vita-Salute San Raffaele, Milano, Italy

    P Ghia

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  1. L R Martins
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Correspondence to J T Barata.

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Competing interests

RS and DD are employees of Cylene Pharmaceuticals. The remaining authors declare no conflict of interest.

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Martins, L., Lúcio, P., Melão, A. et al. Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia. Leukemia 28, 179–182 (2014). https://doi.org/10.1038/leu.2013.232

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