An Evaluation of the Presence, Type and Suggestions About the Mechanisms of Drug Interaction Between Venetoclax and GSK595 in Multiple Myeloma

Multiple myeloma (MM) is the second most prevalent blood cancer in Singapore. Although the BH3-mimetic Venetoclax is effective against MM, acquired drug resistance occurs due to a shift in the balance between the activities of pro- and anti-apoptotic Bcl-2 family proteins towards survival. Here, we investigate whether the protein arginine methyltransferase 5 (PRMT5) inhibitor GSK3326595 can synergise with Venetoclax by modulating the activities of pro- and anti-apoptotic Bcl-2 family proteins. Using the Zero interaction potency (ZIP) model, we demonstrate the potential synergy between Venetoclax and GSK3326595 on several MM cell lines. Using flow cytometry and gene expression analysis, we also elucidated possible mechanisms of synergy and a seemingly counterintuitive gene expression pattern, which collectively suggest that both drugs likely induce apoptosis at the post-translational level.