PI3K/AKT confers intrinsic and acquired resistance to pirtobrutinib in chronic lymphocytic leukemia

Pirtobrutinib, a non-covalent Bruton's tyrosine kinase (BTK) inhibitor, has been approved as the first agent to overcome resistance to covalent BTK inhibitors (such as ibrutinib, acalabrutinib, and zanubrutinib). However, the mechanisms of pirtobrutinib resistance in chronic lymphocytic leukemia (CLL) remain poorly understood.