Strategies for overcoming resistance to Bruton's tyrosine kinase inhibitor zanubrutinib

Abstract Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B‐cell malignancies. They target BTK, a key effector in the B‐cell receptor (BCR) signaling pathway, crucial for B‐cell survival and proliferation. The first‐in‐class irreversible BTK inhibitor, ibrutinib, was approved for various B‐cell malignancies but has limitations due to off‐target effects. Second‐generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti‐CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis‐targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK‐targeted therapies provide hope for improved outcomes in patients with B‐cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.