Thijssen, Rachel ORCID: 0000-0002-4493-306X, ter Burg, Johanna, Garrick, Brett, van Bochove, Gregor G. W., Brown, Jennifer R., Fernandes, Stacey M., Sole Rodriguez, Maria, Michot, Jean-Marie ORCID: 0000-0003-3482-3331, Hallek, Michael, Eichhorst, Barbara, Reinhardt, Hans Christian, Bendell, Johanna, Derks, Ingrid A. M., van Kampen, Roel J. W., Hege, Kristen, Kersten, Marie Jose, Trowe, Torsten, Filvaroff, Ellen H., Eldering, Eric and Kater, Arnon P. (2016). Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood, 128 (4). S. 574 - 584. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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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, drugswith 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 proteinkinase (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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Thijssen, RachelUNSPECIFIEDorcid.org/0000-0002-4493-306XUNSPECIFIED
ter Burg, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garrick, BrettUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Bochove, Gregor G. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brown, Jennifer R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandes, Stacey M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sole Rodriguez, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Michot, Jean-MarieUNSPECIFIEDorcid.org/0000-0003-3482-3331UNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichhorst, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bendell, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Derks, Ingrid A. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Kampen, Roel J. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hege, KristenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kersten, Marie JoseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trowe, TorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Filvaroff, Ellen H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eldering, EricUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kater, Arnon P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-269436
DOI: 10.1182/blood-2016-02-700328
Journal or Publication Title: Blood
Volume: 128
Number: 4
Page Range: S. 574 - 584
Date: 2016
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DEPENDENT PROTEIN-KINASE; DNA-REPAIR PATHWAYS; CELL-CYCLE; CLL CELLS; B-CELLS; DAMAGE RESPONSE; T-CELLS; RESISTANCE; APOPTOSIS; SURVIVALMultiple languages
HematologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/26943

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