BTK Inhibitor Success Puts Focus on Resistance Mechanisms

Krithika Subramanian, PhD
Published: Tuesday, Oct 02, 2018
Krithika Subramanian, PhD

Krithika Subramanian, PhD

Less than 5 years after Bruton tyrosine kinase (BTK) inhibition was introduced in hematologic malignancies, the need for strategies to address primary and secondary mechanisms of resistance has emerged.


Targeting BTK in Cancer

The identification of BTK as a target for anticancer therapy stems from its involvement in aberrant B-cell receptor (BCR) signaling, which plays a central role in B-cell malignancies. BCR signaling is initiated by antigen binding, resulting in receptor aggregation and subsequent phosphorylation of the cytoplasmic tyrosine-based activation motifs in BCR by the SRC family kinases SYK and LYN.

Figure. BCR Signaling and Key Factors Involved in Ibrutinib Resistance

Figure. BCR Signaling and Key Factors Involved in Ibrutinib Resistance
This helps drive BTK to amplify and transmit BCR signaling, through phosphorylation of phospholipase C gamma 2 (PLC-gamma-2), mobilization of calcium secondary messenger, and activation of transcriptional programs driven by the nuclear factor к-B (NF–кB), AKT, RAS, mitogen-activated protein kinase, and nuclear factor of activated T cells pathways, ultimately promoting B-cell proliferation and survival (Figure).1,2

Ibrutinib Enters the Picture 

Ibrutinib was initially approved for patients with MCL as a secondline monotherapy and has since gained indications in chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), and Waldenström macroglobulinemia (WM) as first-line therapy, as well as in marginal zone lymphoma (MZL) and chronic graft versus host disease after at least 1 prior therapy.7

Table. The Landscape of BTK Inhibitors

Table. The Landscape of BTK Inhibitors
Ibrutinib inactivates BTK by binding covalently to cysteine 481 (C481) within the ATP-binding pocket in the kinase domain, acting as an irreversible inhibitor.8 Ibrutinib–BTK binding inhibits phosphorylation of BTK and its downstream targets and abrogates downstream BCR signaling. The potent activity of ibrutinib, first in MCL and subsequently in CLL, paired with the drugs relative tolerability underscores a paradigm shift in the treatment of aggressive B-cell malignancies.9
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Oncology Briefings™: Individualizing Treatment After Second-Line Therapy for Patients With mCRCAug 29, 20191.0
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