Targeting Venetoclax-Resistant CLL by Bcl-XL Degradation

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults and is associated with resistance to apoptosis. Clinical responses are dramatically improved with the use of targeted therapies such as venetoclax, a selective inhibitor of the anti-apoptotic protein Bcl-2, compared to chemoimmunotherapy. However, some patients can ultimately develop resistant CLL. Bcl-xL overexpression has been implicated in multiple mechanisms of venetoclax resistance, representing a switch that confers cell survival despite Bcl-2 inhibition. Mechanisms of venetoclax resistance include mutated Bcl-2 (ex. G101V), switches in survival dependence to alternative BCL2 family members, and microenvironmental interactions (Reviewed in Bose et al., 2017). Moreover, disease progression on venetoclax is accelerated in CLL patients with aberrant p53 , and our laboratory identified Bcl-xL as one of the main contributors to the oncogenic abilities of mutant p53.Thus, Bcl-xL is a promising target for re-sensitizing CLL to apoptosis, but since it is crucial for platelet viability, direct targeting has not been clinically successful.