PMID- 27235137 OWN - NLM STAT- MEDLINE DCOM- 20170803 LR - 20211204 IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 128 IP - 4 DP - 2016 Jul 28 TI - Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. PG - 574-83 LID - 10.1182/blood-2016-02-700328 [doi] AB - 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. CI - (c) 2016 by The American Society of Hematology. FAU - Thijssen, Rachel AU - Thijssen R AD - Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; FAU - Ter Burg, Johanna AU - Ter Burg J AD - Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; FAU - Garrick, Brett AU - Garrick B AD - Celgene, San Francisco, CA; FAU - van Bochove, Gregor G W AU - van Bochove GG AD - Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; FAU - Brown, Jennifer R AU - Brown JR AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; FAU - Fernandes, Stacey M AU - Fernandes SM AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; FAU - Rodriguez, Maria Sole AU - Rodriguez MS AD - Department of Hematology, Hospital Universitario Virgen del Rocio, Seville, Spain; FAU - Michot, Jean-Marie AU - Michot JM AD - Department of Hematology, Institut Gustave Roussy, Villejuif, France; FAU - Hallek, Michael AU - Hallek M AD - Department of Hematology, University Hospital, Cologne, Germany; FAU - Eichhorst, Barbara AU - Eichhorst B AD - Department of Hematology, University Hospital, Cologne, Germany; FAU - Reinhardt, Hans Christian AU - Reinhardt HC AD - Department of Hematology, University Hospital, Cologne, Germany; FAU - Bendell, Johanna AU - Bendell J AD - Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; FAU - Derks, Ingrid A M AU - Derks IA AD - Department of Experimental Immunology and. FAU - van Kampen, Roel J W AU - van Kampen RJ AD - Orbis Medisch Centrum, Sittard, The Netherlands; and. FAU - Hege, Kristen AU - Hege K AD - Celgene, San Francisco, CA; FAU - Kersten, Marie Jose AU - Kersten MJ AD - Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam, The Netherlands. FAU - Trowe, Torsten AU - Trowe T AD - Celgene, San Francisco, CA; FAU - Filvaroff, Ellen H AU - Filvaroff EH AD - Celgene, San Francisco, CA; FAU - Eldering, Eric AU - Eldering E AD - Department of Experimental Immunology and Lymphoma and Myeloma Center Amsterdam, The Netherlands. FAU - Kater, Arnon P AU - Kater AP AD - Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam, The Netherlands. LA - eng SI - ClinicalTrials.gov/NCT01353625 PT - Clinical Trial PT - Journal Article DEP - 20160527 PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Bridged Bicyclo Compounds, Heterocyclic) RN - 0 (Neoplasm Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Purines) RN - 0 (Pyrazines) RN - 0 (Quinazolinones) RN - 0 (Sulfonamides) RN - 0 (Triazoles) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (DNA-Activated Protein Kinase) RN - EC 2.7.11.1 (PRKDC protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - FA2DM6879K (Vidarabine) RN - FII75TFH5L (1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one) RN - N54AIC43PW (venetoclax) RN - P2K93U8740 (fludarabine) RN - YG57I8T5M0 (idelalisib) SB - IM CIN - Blood. 2016 Jul 28;128(4):470-1. PMID: 27471232 MH - Bridged Bicyclo Compounds, Heterocyclic/pharmacology MH - DNA-Activated Protein Kinase/*antagonists & inhibitors/metabolism MH - Drug Resistance, Neoplasm/*drug effects MH - Female MH - Humans MH - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/enzymology/pathology MH - Male MH - Neoplasm Proteins/*antagonists & inhibitors/metabolism MH - Nuclear Proteins/*antagonists & inhibitors/metabolism MH - Purines/pharmacology MH - Pyrazines/*pharmacology MH - Quinazolinones/pharmacology MH - Sulfonamides/pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Triazoles/*pharmacology MH - Tumor Cells, Cultured MH - Vidarabine/analogs & derivatives/pharmacology EDAT- 2016/05/29 06:00 MHDA- 2017/08/05 06:00 CRDT- 2016/05/29 06:00 PHST- 2016/02/16 00:00 [received] PHST- 2016/05/20 00:00 [accepted] PHST- 2016/05/29 06:00 [entrez] PHST- 2016/05/29 06:00 [pubmed] PHST- 2017/08/05 06:00 [medline] AID - S0006-4971(20)34311-1 [pii] AID - 10.1182/blood-2016-02-700328 [doi] PST - ppublish SO - Blood. 2016 Jul 28;128(4):574-83. doi: 10.1182/blood-2016-02-700328. Epub 2016 May 27.