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Abstract
Ibrutinib is a potent, small-molecule Bruton tyrosine kinase (BTK) inhibitor developed for the treatment of B-cell malignancies. Ibrutinib covalently binds to Cys481 in the ATP-binding domain of BTK. This cysteine residue is conserved among 9 other tyrosine kinases, including HER2 and EGFR, which can be targeted. Screening large panels of cell lines demonstrated that ibrutinib was growth inhibitory against some solid tumor cells, including those inhibited by other HER2/EGFR inhibitors. Among sensitive cell lines, breast cancer lines with HER2 overexpression were most potently inhibited by ibrutinib (<100 nmol/L); in addition, the IC50s were lower than that of lapatinib and dacomitinib. Inhibition of cell growth by ibrutinib coincided with downregulation of phosphorylation on HER2 and EGFR and their downstream targets, AKT and ERK. Irreversible inhibition of HER2 and EGFR in breast cancer cells was established after 30-minute incubation above 100 nmol/L or following 2-hour incubation at lower concentrations. Furthermore, ibrutinib inhibited recombinant HER2 and EGFR activity that was resistant to dialysis and rapid dilution, suggesting an irreversible interaction. The dual activity toward TEC family (BTK and ITK) and ERBB family kinases was unique to ibrutinib, as ERBB inhibitors do not inhibit or covalently bind BTK or ITK. Xenograft studies with HER2+ MDA-MB-453 and BT-474 cells in mice in conjunction with determination of pharmacokinetics demonstrated significant exposure-dependent inhibition of growth and key signaling molecules at levels that are clinically achievable. Ibrutinib's unique dual spectrum of activity against both TEC family and ERBB kinases suggests broader applications of ibrutinib in oncology. Mol Cancer Ther; 15(12); 2835-44. ©2016 AACR.
Highlights
Ibrutinib is a tyrosine kinase inhibitor (TKI) designed primarily to target Bruton tyrosine kinase (BTK), which is expressed predominantly in the B-lymphocytic and myelomonocytic lineages [1]
ERBB family kinases are among those kinases with homologous active site cysteines, Cys797 in EGFR, Cys805 in ERBB2 (HER2), and Cys803 in ERBB4 (HER4), which have been known to be sensitive to ibrutinib in biochemical assays since its discovery [1]
Given the shared activity of ibrutinib and other ERBB kinase inhibitors described earlier and the sequence homologies around the conserved cysteine residue for TEC and ERBB family kinases, we explored whether those ERBB inhibitors had detectable activity against BTK and inducible T-cell kinase (ITK)
Summary
Ibrutinib is a tyrosine kinase inhibitor (TKI) designed primarily to target Bruton tyrosine kinase (BTK), which is expressed predominantly in the B-lymphocytic and myelomonocytic lineages [1]. It binds covalently to Cys481 in the kinase domain of BTK and exhibits excellent selectivity, as only 9 other tyrosine kinases have the homologous cysteine residue [1]. Rapid binding of ibrutinib to its target leads to efficient inhibition of BTK without requiring sustained systemic exposure. This property of ibrutinib enables clinically effective and well tolerated once-a-day dosing despite its short plasma half-life in human subjects. ERBB family kinases are among those kinases with homologous active site cysteines, Cys797 in EGFR, Cys805 in ERBB2 (HER2), and Cys803 in ERBB4 (HER4), which have been known to be sensitive to ibrutinib in biochemical assays since its discovery [1]. Grabinski and colleagues [4] recently reported that
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