Understanding and Targeting BCL2-inhibitor Resistance in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) treatment has evolved with the introduction of venetoclax, a selective BCL-2 inhibitor capable of inducing apoptosis in CLL cells. However, resistance has emerged as a significant clinical obstacle. Here, we delineate the multifactorial basis of venetoclax resistance in CLL by exploring genetic mutations, epigenetic alterations, microenvironmental protection, metabolic rewiring, and downstream signaling adaptations. Furthermore, we examine strategies to overcome resistance, including drug combinations, next-generation BCL-2 inhibitors, and novel immunotherapeutic approaches. Finally, we consider the clinical implications of emerging resistance patterns and discuss future directions in a personalized therapy.