title: Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia.
abstract: 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.
authors.affiliation: Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Rachel
authors.initials: R
authors.lastname: Thijssen
authors.affiliation: Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Johanna
authors.initials: J
authors.lastname: Ter Burg
authors.affiliation: Celgene, San Francisco, CA;
authors.forename: Brett
authors.initials: B
authors.lastname: Garrick
authors.affiliation: Department of Experimental Immunology and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Gregor G W
authors.initials: GG
authors.lastname: van Bochove
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Fernandes
authors.affiliation: Department of Hematology, Hospital Universitario Virgen del Rocío, Seville, Spain;
authors.forename: María Solé
authors.initials: MS
authors.lastname: Rodríguez
authors.affiliation: Department of Hematology, Institut Gustave Roussy, Villejuif, France;
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Michot
authors.affiliation: Department of Hematology, University Hospital, Cologne, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Department of Hematology, University Hospital, Cologne, Germany;
authors.forename: Barbara
authors.initials: B
authors.lastname: Eichhorst
authors.affiliation: Department of Hematology, University Hospital, Cologne, Germany;
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Reinhardt
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN;
authors.forename: Johanna
authors.initials: J
authors.lastname: Bendell
authors.affiliation: Department of Experimental Immunology and.
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Derks
authors.affiliation: Orbis Medisch Centrum, Sittard, The Netherlands; and.
authors.forename: Roel J W
authors.initials: RJ
authors.lastname: van Kampen
authors.affiliation: Celgene, San Francisco, CA;
authors.forename: Kristen
authors.initials: K
authors.lastname: Hege
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam, The Netherlands.
authors.forename: Marie José
authors.initials: MJ
authors.lastname: Kersten
authors.affiliation: Celgene, San Francisco, CA;
authors.forename: Torsten
authors.initials: T
authors.lastname: Trowe
authors.affiliation: Celgene, San Francisco, CA;
authors.forename: Ellen H
authors.initials: EH
authors.lastname: Filvaroff
authors.affiliation: Department of Experimental Immunology and Lymphoma and Myeloma Center Amsterdam, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Lymphoma and Myeloma Center Amsterdam, The Netherlands.
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011687:Purines; D011719:Pyrazines; D052999:Quinazolinones; D013449:Sulfonamides; D014230:Triazoles; C546842:MTOR protein, human; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D058570:TOR Serine-Threonine Kinases; D014740:Vidarabine; C000601954:1-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; C579720:venetoclax; C024352:fludarabine; C552946:idelalisib