Bruton’s Tyrosine Kinase Inhibitors: The Next Frontier of B-Cell-Targeted Therapies for Cancer, Autoimmune Disorders, and Multiple Sclerosis

Abstract

Bruton’s tyrosine kinase (BTK) is an important protein belonging to the tyrosine kinase family that plays a key role in the intracellular signaling and proliferation, migration, and survival of normal and malignant B-lymphocytes and myeloid cells. Understanding the role of BTK in the B-cell signaling pathway has led to the development of BTK inhibitors (BTKi) as effective therapies for malignancies of myeloid origin and exploration as a promising therapeutic option for other cancers. Given its central function in B-cell receptor signaling, inhibition of BTK is an attractive approach for the treatment of a wide variety of autoimmune diseases that involve aberrant B-cell function including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Here, we review the role of BTK in different cell signaling pathways, the development of BTKi in B-cell malignancies, and their emerging role in the treatment of MS and other autoimmune disorders.

PROTACs: A novel strategy for cancer drug discovery and development

“…Bruton's tyrosine kinase (BTK), nonreceptor cytoplasmic tyrosine kinase, is a key regulator in the B-cell receptor (BCR) signaling pathway. 374,375 BTK plays a key role in B-cell lymphomas and is a validated target for mantle cell lymphoma (MCL). Although BTK inhibitors are clinically effective in cancer therapy, drug resistance remains a major challenge.…”

“…BTK plays a key role in B‐cell lymphomas and is a validated target for mantle cell lymphoma (MCL). Although BTK inhibitors are clinically effective in cancer therapy, drug resistance remains a major challenge 374,376 . For example, ibrutinib, a covalent inhibitor approved by the US FDA in 2013, was used to treat MCL and ABC‐DLBCL in patients who have developed resistance due to a C481S missense BTK mutation 377 …”

“…Although BTK inhibitors are clinically effective in cancer therapy, drug resistance remains a major challenge. 374,376 For example, ibrutinib, a covalent inhibitor approved by the US FDA in 2013, was used to treat MCL and ABC-DLBCL in patients who have developed resistance due to a C481S missense BTK mutation. 377 Currently, a variety of noncovalent degraders have been developed that can effectively degrade wild-type and Ibrutinib-resistant C481S BTKS, which may be an effective solution to the problem of serious resistance to BTK inhibitors.…”

Inborn errors of human B cell development, differentiation, and function

“…These observations established that agammaglobulinemia caused recurrent infections, and serum gammaglobulin contained Ab capable of preventing infection. It cannot be emphasized enough that these observations in a single patient not only pre-dated by 4 yr the serendipitous finding by Glick and colleagues that the Bursa of Fabricius was required for generating Ab responses in chickens ( Glick et al, 1956 ), and the formal discovery of B cells by Max Cooper by >10 yr ( Cooper et al, 1965 ), but also led to the findings that: X-linked agammaglobulinemia (XLA) is caused by mutations in BTK ( Conley et al, 2009 ); Bruton’s tyrosine kinase (BTK) links the BCR to many intracellular signaling pathways and is critical for human B cell development and function; Ab deficiency can be treated by Ig replacement therapy irrespective of genetic cause; and Pharmacological targeting of BTK would revolutionize treatment for B cell malignancies and some autoimmune conditions decades later ( Garg et al, 2022 ; Gayko et al, 2015 ). …”

“…Pharmacological targeting of BTK would revolutionize treatment for B cell malignancies and some autoimmune conditions decades later ( Garg et al, 2022 ; Gayko et al, 2015 ).…”