Resistance to noncovalent BTK inhibitors is mediated by non-C481 BTK and PLCγ2 mutations.

  • Major Finding: Resistance to noncovalent BTK inhibitors is mediated by non-C481 BTK and PLCγ2 mutations.

  • Concept: These mutations impair drug binding as well as allow effective signaling despite hindering BTK catalytic activity.

  • Impact: New mechanisms of escape were demonstrated that confer resistance to both noncovalent and covalent BTK inhibitors.

Use of covalent or irreversible inhibitors of Bruton tyrosine kinase (BTK) in patients with chronic lymphocytic leukemia (CLL) has improved survival outcomes, but resistance can be acquired through mutation at the C481 residue, which impairs drug binding. Noncovalent or reversible BTK inhibitors have been developed that do not require C481 residue binding and therefore allow effective inhibition of C481-mutant BTK. However, knowledge of the mechanisms of resistance to non­covalent BTK inhibitors is lacking. Wang, Mi, Thompson, Mato, Taylor, Abdel-Wahab, and colleagues, therefore, investigated these mechanisms of resistance in nine patients with relapsed or refractory CLL treated with pirtobrutinib as part of the phase I/II BRUIN clinical trial. Using genomic analysis of patient samples from both pretreatment and time-of-progression time points, seven of the nine patients were found to have acquired new BTK kinase domain mutations outside of the C481 residue that were not present at the start of treatment. These mutations included V416L, A428D, M437R, T474I, and L528W, with no new C481 mutations being demonstrated. The remaining two patients presented mutations in the BTK downstream effector, PLCγ2. Functional characterization of these new non-C481 BTK mutations showed their association with resistance to multiple noncovalent BTK inhibitors by impairing drug binding. Examination on the effects of these mutations on BTK autophosphorylation, a marker of catalytic activity, revealed that these mutations diminished autophosphorylation, but downstream signaling was still activated. Furthermore, some of these mutations, including A428D and L528W, also conferred resistance to covalent BTK inhibitors. Therefore, this study demonstrates the mechanisms of resistance behind non­covalent BTK inhibitors and suggests the need to develop new therapeutic approaches to overcome this resistance, potentially through development of inhibitors targeting the scaffold function of BTK instead of its kinase function. Further analyses of a larger sample size as well as resistance mechanisms of previously untreated patients continue to remain necessary.

Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, et al. Mechanisms of resistance to noncovalent Bruton's tyrosine kinase inhibitors. N Engl J Med 2022;386:735–43.

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