Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia.

Autor:	Thijssen R; Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;, Ter Burg J; Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;, Garrick B; Celgene, San Francisco, CA;, van Bochove GG; Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;, Brown JR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;, Fernandes SM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;, Rodríguez MS; Department of Hematology, Hospital Universitario Virgen del Rocío, Seville, Spain;, Michot JM; Department of Hematology, Institut Gustave Roussy, Villejuif, France;, Hallek M; Department of Hematology, University Hospital, Cologne, Germany;, Eichhorst B; Department of Hematology, University Hospital, Cologne, Germany;, Reinhardt HC; Department of Hematology, University Hospital, Cologne, Germany;, Bendell J; Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN;, Derks IA; Department of Experimental Immunology and., van Kampen RJ; Orbis Medisch Centrum, Sittard, The Netherlands; and., Hege K; Celgene, San Francisco, CA;, Kersten MJ; Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam, The Netherlands., Trowe T; Celgene, San Francisco, CA;, Filvaroff EH; Celgene, San Francisco, CA;, Eldering E; Department of Experimental Immunology and Lymphoma and Myeloma Center Amsterdam, The Netherlands., Kater AP; Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2016 Jul 28; Vol. 128 (4), pp. 574-83. Date of Electronic Publication: 2016 May 27.
DOI:	10.1182/blood-2016-02-700328
Abstrakt:	Inhibition of B-cell receptor (BCR) signaling pathways in chronic lymphocytic leukemia (CLL) provides significant clinical benefit to patients, mainly by blocking adhesion of CLL cells in the lymph node microenvironment. The currently applied inhibitors ibrutinib and idelalisib have limited capacity however to induce cell death as monotherapy and are unlikely to eradicate the disease. Acquired resistance to therapy in CLL is often caused by mutations in the response network being targeted, both for DNA damage or BCR signaling pathways. Thus, drugs with dual targeting capacity could offer improved therapeutic value. Here, the potency of CC-115, a novel inhibitor of mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK), was evaluated in primary CLL cells in vitro and in CLL patients. Combined TORK and DNA-PK inhibition in vitro resulted in caspase-dependent cell killing irrespective of p53, ATM, NOTCH1, or SF3B1 status. Proliferation induced by CD40(+) interleukin-21 stimulation was completely blocked by CC-115, and CD40-mediated resistance to fludarabine and venetoclax could be reverted by CC-115. BCR-mediated signaling was inhibited by CC-115 and also in CLL samples obtained from patients with acquired resistance to idelalisib treatment. Clinical efficacy of CC-115 was demonstrated in 8 patients with relapsed/refractory CLL/small lymphocytic lymphoma harboring ATM deletions/mutations; all but 1 patient had a decrease in lymphadenopathy, resulting in 1 IWCLL partial response (PR) and 3 PRs with lymphocytosis. In conclusion, these preclinical results, along with early promising clinical activity, suggest that CC-115 may be developed further for treatment of CLL. The trial was registered at www.clinicaltrials.gov as #NCT01353625. (© 2016 by The American Society of Hematology.)
Databáze:	MEDLINE
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