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.

The robust potency of ibrutinib (Imbruvica), which, in December 2013, became the first BTK inhibitor to gain FDA approval, has paved the way for second-generation agents with improved specificity profiles and expanded the potential for adding the drug to novel combination therapies. Ibrutinib use in a wider range of patients has also revealed the significance of resistance mechanisms and the need for options to manage ibrutinib-resistant cancers.

In October, the FDA approved acalabrutinib (Calquence), another BTK inhibitor, as second-line therapy in mantle cell lymphoma (MCL). Several other BTK-targeting drugs, including agents designed to address resistance mutations, are being investigated in clinical studies (Table).

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

BTK is a member of the highly conserved TEC kinase family.3,4 BTK loss-of-function mutations result in X-linked agammaglobulinemia, characterized by absence of B cells, low serum immunoglobulin levels, and recurring infections, all consequences of impaired B-cell development. In addition to its role in BCR signaling, BTK is involved in chemokine-receptor, toll-like receptor, and Fc-receptor signaling in B cells.1,5

The expression of BTK in B-cell malignancies and its pivotal role in the BCR signaling cascade, B-cell development, and lymphomagenesis mark BTK as a unique druggable target, providing a compelling rationale for use of BTK inhibitors in hematological malignancies.6

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

In CLL, ibrutinib has been a transformative therapy. The FDA approval of ibrutinib in CLL, for patients who had received at least 1 prior therapy and for previously untreated patients, was based on significantly improved overall survival (OS) compared with standard-of-care therapies.10,11

In the first-line setting in CLL, the OS rate at 24 months among participants in the phase III RESONATE-2 study was 98% for patients treated with ibrutinib versus 85% among those treated with standard-of-care chlorambucil, which translated to an 84% reduction in the risk of death (HR, 0.16; 95% CI, 0.05-0.56; P = .001).10


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