Burgeoning Data on BTK Inactivating Mutations in Lymphomagenesis and Therapeutic Resistance

Abstract

The B-cell antigen receptor signaling pathway has been a primary focus in the targeted treatment of B-cell malignancies for the past decade. When aberrantly activated, this pathway initiates a cascade of phosphorylation mediated by several tyrosine kinases, with Bruton’s tyrosine kinase (BTK) being essential among them. Multiple generations of covalent and non-covalent BTK inhibitors have revolutionized therapeutic options for several B-cell lymphomas. However, the use of continuous BTK inhibition is limited by development of resistance resulting from acquired point mutations that allow persistent B-cell receptor signaling. Genomic sequencing of patient samples at disease progression has recently led to the discovery of novel resistance mutations in BTK that result in diminished or absent BTK kinase activity (termed kinase-deficient). However, the mechanisms underlying the potential advantage of kinase-deficient BTK mutations are incompletely understood and still under investigation. In this review, we provide a background of the pathway leading to the development of current therapies that target BTK and review the literature describing kinase-deficient BTK mutations. We propose that BTK inactivating mutations provide an advantage to neoplastic B-lymphocytes in patients with BTK inhibitor resistant B-cell malignancies and highlight potential mechanisms through which BTK kinase-deficient mutations could be acting, either due to differential protein conformation or by behaving as a scaffold for other signaling molecules. Due to the novelty of these mutations and their increasing rate of incidence over the last decade, it is imperative to continue studying BTK kinase deficient mutations across B-cell malignancies and to propose alternate therapies that could target them.