In lymphoid malignancies including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), “hyperphosphorylation of BCL-2 family proteins, including anti-apoptotic MCL-1 and BCL-2 and pro-apoptotic BAD and BAX, underlies functional mechanisms of both intrinsic and acquired resistance of venetoclax,” according to a study published in the Journal of Clinical Investigation.
The report stated that patients with CLL can develop resistance over time, while patients with DLBCL and other malignancies are often inherently resistant to venetoclax. Lead author, Stephen Jun Fei Chong, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, noted that previously described mechanisms of genomic resistance such as BCL-2 mutations likely only apply to a subset of venetoclax resistance.
Drivers of Venetoclax Resistance Identified in Lymphoid Malignancies
Researchers used BH3-profiling and high throughput-kinase activity mapping to identify the role of anti-apoptotic BCL-2 family protein hyperphosphorylation. They further established that this phosphorylation altered apoptotic protein interactions and altered functional dependence on anti-apoptotic proteins.
Notably, targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs, such as FTY720, was able to restore sensitivity to venetoclax across treatment-resistant lymphoid cell lines, a resistant mouse model, and paired patients samples from before venetoclax initiation and at time of progression.
In closing, Dr. Chong and colleagues suggested their findings “could further assist in identifying lead compounds or repurposing [Food and Drug Administration]-approved drugs… based on their potential to activate [protein phosphatase 2]/inhibit kinases, reduce BCL-2 family protein phosphorylation, and rewire survival dependences towards BCL-2 for venetoclax-induced cell death.”
Reference
Chong SJF, Zhu F, Dashevsky O, et al. Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies. J Clin Invest. 2023;e170169. doi:10.1172/JCI170169