Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib

New England Journal of Medicine (Impact Factor: 55.87). 05/2014; 370(24). DOI: 10.1056/NEJMoa1400029
Source: PubMed

ABSTRACT Background:
Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance.

We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis.

We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib.

Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).

42 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: B-cell receptor (BCR) inhibitors represent an exciting new treatment modality in chronic lymphocytic leukemia (CLL). Currently, ibrutinib monotherapy as well as idelalisib in combination with rituximab are approved by the European Medical Agency for the treatment of all patients with relapsed/refractory CLL and for first-line treatment of patients with deletion 17p or TP53 mutation unsuitable for chemoimmunotherapy. The results of ongoing trials with these and other BCR inhibitors are expected to lay the basis for approval in further indications, but have to be awaited. Above all, BCR inhibitors have shown to be able to fill the gap of urgently needed therapies for the elderly and comorbid CLL patient as well as the CLL patient with deletion 17p. BCR inhibitors might also challenge the role of allogeneic stem cell transplantation in CLL in the future.
    memo - Magazine of European Medical Oncology 04/2014; 8(1):38-42. DOI:10.1007/s12254-014-0186-0
  • [Show abstract] [Hide abstract]
    ABSTRACT: To the Editor: Ibrutinib, an inhibitor that binds covalently to C481 of Bruton's tyrosine kinase (BTK), has produced remarkable responses in patients with relapsed and refractory chronic lymphocytic leukemia (CLL).(1)-(4) However, 5.3% of patients have disease progression, and the mechanism of resistance is largely unknown. Herein we describe the mechanism of resistance in such a case. A 49-year-old woman had a diagnosis of CLL established in 2000. After the failure of multiple treatments, she began receiving ibrutinib at a dose of 560 mg daily in 2010 as part of a phase 1, dose-escalation study of ibrutinib in B-cell cancers. . . .
    New England Journal of Medicine 05/2014; 370(24). DOI:10.1056/NEJMc1402716 · 55.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia has been successful with durable remissions observed with several targeted therapeutics. Protein Kinase C-β (PKC-β) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters β-catenin expression, resulting in decreased downstream transcriptional genes as cMyc, cyclin D1 and CD44. Lastly, our preliminary in vivo studies indicate beneficial anti-tumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-β has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted.
    Blood 07/2014; 124(9). DOI:10.1182/blood-2014-05-574830 · 10.45 Impact Factor
Show more


42 Reads
Available from