A BTK mutation in ibrutinib-resistant patients prevents ibrutinib from binding irreversibly.
Major finding: A BTK mutation in ibrutinib-resistant patients prevents ibrutinib from binding irreversibly.
Mechanism: Gain-of-function PLCG2 mutations allow BTK-independent B-cell receptor signaling.
Impact: Understanding ibrutinib resistance mechanisms can guide efforts to treat or prevent resistant disease.
The irreversible Bruton tyrosine kinase (BTK) inhibitor ibrutinib has shown significant clinical activity in patients with relapsed and refractory chronic lymphocytic leukemia (CLL), with over half of treated patients experiencing a complete or partial response. Although few ibrutinib-treated patients have relapsed to date, as the number of patients receiving ibrutinib increases it is crucial to characterize ibrutinib resistance mechanisms in order to devise treatment strategies for those who have relapsed and guide development of combination approaches to prevent resistance from developing. Woyach and colleagues performed whole-exome sequencing on peripheral blood samples at baseline and relapse from 6 patients with ibrutinib-resistant CLL. Strikingly, 5 of 6 patients had acquired a C481S mutation in BTK affecting the residue to which ibrutinib binds, and 2 patients had distinct mutations in phospholipase C gamma 2 (PLCG2), which encodes a kinase that acts immediately downstream of BTK in the B-cell receptor (BCR) signaling pathway. The C481S mutation significantly reduced the affinity of ibrutinib for BTK and prevented its irreversible binding, leading to diminished inhibition of signaling downstream of BTK upon BCR activation in vitro. The PLCG2 mutations also were found to reduce ibrutinib sensitivity in vitro, but appeared to have a gain-of-function effect, as they promoted BTK-independent BCR pathway activation in the presence of ibrutinib. These findings reveal a tyrosine kinase inhibitor resistance mechanism that is distinct from other mechanisms involving secondary mutations in the target kinase; instead, ibrutinib resistance can arise from a primary mutation in the target kinase or its immediate downstream target, neither of which are recurrently mutated in CLL. Although additional ibrutinib resistance mechanisms likely remain to be discovered, this characterization of patients who have relapsed on ibrutinib may help initiate strategies to prevent or overcome ibrutinib resistance.
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