New roles for B cell receptor associated kinases: when the B cell is not the target

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• B cell receptor associated kinases (BAKs), including Bruton's tyrosine kinase (BTK) and phosphoinositol-3-kinase (PI3K) delta, are crucial for B cell signaling.
• Targeted inhibitors of BAKs have transformed B lymphoid malignancy treatment.
• While mutations in BTK are linked to therapy resistance in chronic lymphocytic leukemia (CLL), BAKs are rarely mutated in treatment-naïve lymphomas, questioning their role as primary drivers.

Purpose of the Study:

• To review and validate the role of BAK inhibitors in cancer therapy.
• To explore the impact of BAK inhibitors on the tumor microenvironment (TME).
• To discuss the potential of BAK inhibitors in treating both hematological and solid tumors.

Main Methods:

• Literature review and synthesis of existing research on BAK inhibitors.
• Analysis of data regarding mutations in BAKs and their clinical relevance.
• Examination of preclinical models, including murine CLL models, to understand BAK function.

Main Results:

• BAK inhibitors have shown significant efficacy in B lymphoid malignancies.
• Evidence suggests BAKs play a role in shaping the dialogue between malignant B cells and the TME.
• BAK inhibitors can induce lymphoid cell redistribution, explaining observed increases in peripheral blood counts.
• BAK inhibitors also demonstrate efficacy in solid tumors, likely via modulation of TME mediator cells.

Conclusions:

• BAK inhibitors represent a class of agents that modulate the cancer-associated (hematopoietic) microenvironment.
• Their impact on the TME offers a novel therapeutic strategy for various cancers.
• Further research is warranted to fully elucidate the mechanisms and expand the application of BAK inhibitors.