Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors

Background Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. Methods We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. Results Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors.Conclusions Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.

A Unified Nomenclature for Injectisome-Type Type III Secretion Systems

The independent naming of components of injectisome-type type III secretion systems in different bacterial species has resulted in considerable confusion, impeding accessibility of the literature and hindering communication between scientists of the same field. A unified nomenclature had been proposed by Hueck more than 20 years ago. It found little attention for many years, but usage was sparked again by recent reviews and an international type III secretion meeting in 2016. Here, we propose that the field consistently switches to an extended version of this nomenclature to be no longer lost in translation

Assembly and Post-assembly Turnover and Dynamics in the Type III Secretion System

The type III secretion system (T3SS) is one of the largest transmembrane complexes in bacteria, comprising several intricately linked and embedded substructures. The assembly of this nanomachine is a hierarchical process which is regulated and controlled by internal and external cues at several critical points. Recently, it has become obvious that the assembly of the T3SS is not a unidirectional and deterministic process, but that parts of the T3SS constantly exchange or rearrange. This article aims to give an overview on the assembly and post-assembly dynamics of the T3SS, with a focus on emerging general concepts and adaptations of the general assembly pathway