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

Rachel Thijssen, Johanna ter Burg, Brett Garrick, Gregor G.W. van Bochove, Jennifer R. Brown, Stacey M. Fernandes, María Solé Rodríguez, Jean-Marie Michot, Michael Hallek, Barbara Eichhorst, Hans Christian Reinhardt, Johanna Bendell, Ingrid A.M. Derks, Roel J.W. van Kampen, Kristen Hege, Marie José Kersten, Torsten Trowe, Ellen H. Filvaroff, Eric Eldering and Arnon P. Kater

Key points

  • TORK/DNA-PK inhibition induces cytotoxicity and blocks signaling pathways important for CLL survival, proliferation and drug resistance.

  • Preliminary clinical effects of TORK/DNA-PK inhibition show 7/8 CLL patients with decreased lymphadenopathy.

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 (LN) 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+IL-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, also in CLL samples obtained from patients with acquired resistance to idelalisib treatment. Clinical efficacy of CC-115 was demonstrated in eight patients with relapsed/refractory CLL/SLL harboring ATM deletions/mutations; all but one patient had a decrease in lymphadenopathy, resulting in one IWCLL partial response (PR) and three PRs with lymphocytosis. The clinical trial was registered at www.ClinicalTrials.gov as NCT01353625. In conclusion, these preclinical results, along with early promising clinical activity, suggest that CC-115 may be developed further for treatment of CLL.

  • Submitted February 16, 2016.
  • Accepted May 20, 2016.