Efficacy of Mcl-1 Inhibitors in Multiple Myeloma Cells Resistant to Bortezomib

Multiple myeloma (MM) is a type of cancer that affects plasma B cells. Patients with MM often experience frequent relapses and can develop resistance to drugs. As a medical researcher, it is important to understand the role of Mcl-1 in preventing intrinsic apoptosis and drug resistance. Mcl-1 belongs to the anti-apoptotic subgroup of Bcl-2 family proteins and plays a crucial role in these processes. Mcl-1 plays a crucial role in driving disease progression and contributing to drug resistance in MM. It has been observed that there is an increased expression of Mcl-1 in 52% of patients with MM during diagnosis, which further rises to 81% during relapse. Thus, researchers are investigating the potential of Mcl-1 inhibitors as a viable treatment option for patients with MM, particularly those who have not responded to previous therapies. Proteasome inhibitor Bortezomib (BTZ) is commonly prescribed as the initial treatment for MM, but unfortunately, patients eventually develop resistance to it. For this study, we created cells that are resistant to BTZ in order to explore the potential mechanisms behind the development of resistance. These cells have been treated with BTZ over a period of 6 months. Regrettably, there are currently no Mcl-1 inhibitors that have been approved by the FDA. However, there are several agents, such as S63845, AZ5991, and VU661013, that are currently undergoing clinical trials. Interestingly, Mcl-1 inhibitors demonstrated effectiveness against sensitive cells but showed a decrease in efficacy against BTZ resistant cells. Our research indicates that cells resistant to BTZ require a higher concentration of Mcl-1 inhibitors in order to undergo cell death. This suggests that these resistant cells may possess a compensatory mechanism that stabilizes the Mcl-1 protein and alters the effectiveness of Mcl-1 inhibitors in treatment. It is worth noting that the anti-apoptotic Bcl-2 protein exhibits heightened expression in resistant cells, even when inhibitors are present. This observation may provide valuable insights into a potential resistance mechanism and calls for further investigation into the compensatory mechanisms that play a crucial role in drug resistance.