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Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. / Thijssen, Rachel; ter Burg, Johanna; Garrick, Brett et al.

In: Blood, Vol. 128, No. 4, 2016, p. 574-583.

Research output: Contribution to journalArticleAcademicpeer-review

Harvard

Thijssen, R, ter Burg, J, Garrick, B, van Bochove, GGW, Brown, JR, Fernandes, SM, Rodríguez, MS, Michot, J-M, Hallek, M, Eichhorst, B, Reinhardt, HC, Bendell, J, Derks, IAM, van Kampen, RJW, Hege, K, Kersten, MJ, Trowe, T, Filvaroff, EH, Eldering, E & Kater, AP 2016, 'Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia', Blood, vol. 128, no. 4, pp. 574-583. https://doi.org/10.1182/blood-2016-02-700328

APA

Thijssen, R., ter Burg, J., Garrick, B., van Bochove, G. G. W., Brown, J. R., Fernandes, S. M., Rodríguez, M. S., Michot, J-M., Hallek, M., Eichhorst, B., Reinhardt, H. C., Bendell, J., Derks, I. A. M., van Kampen, R. J. W., Hege, K., Kersten, M. J., Trowe, T., Filvaroff, E. H., Eldering, E., & Kater, A. P. (2016). Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood, 128(4), 574-583. https://doi.org/10.1182/blood-2016-02-700328

Vancouver

Author

Thijssen, Rachel ; ter Burg, Johanna ; Garrick, Brett et al. / Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. In: Blood. 2016 ; Vol. 128, No. 4. pp. 574-583.

BibTeX

@article{ed5ee712e3c04ba6ad09d0715bbdfe4e,
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",
author = "Rachel Thijssen and {ter Burg}, Johanna and Brett Garrick and {van Bochove}, {Gregor G. W.} and Brown, {Jennifer R.} and Fernandes, {Stacey M.} and Rodr{\'i}guez, {Mar{\'i}a Sol{\'e}} and Jean-Marie Michot and Michael Hallek and Barbara Eichhorst and Reinhardt, {Hans Christian} and Johanna Bendell and Derks, {Ingrid A. M.} and {van Kampen}, {Roel J. W.} and Kristen Hege and Kersten, {Marie Jos{\'e}} and Torsten Trowe and Filvaroff, {Ellen H.} and Eric Eldering and Kater, {Arnon P.}",
year = "2016",
doi = "10.1182/blood-2016-02-700328",
language = "English",
volume = "128",
pages = "574--583",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "4",

}

RIS

TY - JOUR

T1 - Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia

AU - Thijssen, Rachel

AU - ter Burg, Johanna

AU - Garrick, Brett

AU - van Bochove, Gregor G. W.

AU - Brown, Jennifer R.

AU - Fernandes, Stacey M.

AU - Rodríguez, María Solé

AU - Michot, Jean-Marie

AU - Hallek, Michael

AU - Eichhorst, Barbara

AU - Reinhardt, Hans Christian

AU - Bendell, Johanna

AU - Derks, Ingrid A. M.

AU - van Kampen, Roel J. W.

AU - Hege, Kristen

AU - Kersten, Marie José

AU - Trowe, Torsten

AU - Filvaroff, Ellen H.

AU - Eldering, Eric

AU - Kater, Arnon P.

PY - 2016

Y1 - 2016

N2 - 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

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

U2 - 10.1182/blood-2016-02-700328

DO - 10.1182/blood-2016-02-700328

M3 - Article

C2 - 27235137

VL - 128

SP - 574

EP - 583

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -

ID: 2920525