Posted: Tuesday, April 19, 2022
Stephen J.F. Chong, PhD, of the Dana-Farber Cancer Institute, Boston, and colleagues aimed to determine whether phosphorylation of antiapoptotic proteins BCL2 and MCL1 drive resistance to venetoclax in patients with B-cell malignancies. By removing this modification, the investigators were able to resensitize resistant malignant cells to venetoclax-induced death. These results were presented during the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 3959/4).
“Our work defines a new targetable mechanism of venetoclax resistance in lymphoid malignancies due to the phosphorylation of antiapoptotic BCL2 family proteins,” concluded the study authors. “PP2A-activating drugs resensitize resistant malignant cells to venetoclax treatment via dephosphorylation of antiapoptotic proteins, suggesting a promising combination approach to explore further.”
Western blot, cell death assays, and BH3 profiling (an assay assessing mitochondrial apoptotic priming and antiapoptotic protein dependence) were performed on diffuse large B-cell lymphoma (DLBCL) and diffuse histiocytic lymphoma (DHL) cell lines. DLBCL cell lines were either venetoclax-acquired resistant or sensitive parental; the DHL cell line was inherently resistant.
Compared with the sensitive parental cell line, the venetoclax acquired-resistant DLBCL cell line appeared to have increased protein levels of BCL2-P, MCL1-P, and MCL1; the DHL cell line had higher levels of MCL1-P and MCL1, further demonstrating that an increase in phosphorylation status may induce venetoclax resistance. BH3 profiling showed that antiapoptotic protein phosphorylation–driven resistance involves alterations in sensitivity to these proteins, thus increasing and decreasing sensitivity to MCL1 inhibition and BCL2 inhibition, respectively.
PP2A-activating drugs such as fingolimod (FTY720) were found not only to dissociate BAX from BCL2 and destabilize MCL1 protein, but also seemed to dephosphorylate BCL2-P and MCL1-P. These alterations appeared to rewire cellular sensitivity to BCL2 inhibition, therefore resensitizing these cells to venetoclax-induced death.
Disclosure: For full disclosures of the study authors, visit abstractsonline.com.