ARE THE BCL2 FAMILY INHIBITORS SUBSTRATES FOR THE MULTIDRUG RESISTANCE EFFLUX PUMP MDR1?

Abstract

The BH3 mimetic compounds, a novel class of targeted anti-cancer agents, are highly efficacious for the treatment of certain haematological malignancies. The BCL2 inhibitor, venetoclax, is the most advanced and has been approved for treating patients with high-risk chronic lymphocytic leukemia (CLL) in many countries. While highly effective, clinical resistance is emerging, and we anticipate that resistance to BH3 mimetic therapy will be a problem in the future. Unlike CLL, the BCL2 relative MCL1 is the key survival factor in multiple myeloma (MM) and clinical trials with inhibitors selective for MCL1 have started in patients with this disease. To anticipate what might drive resistance to MCL1 inhibition, we have undertaken studies using model systems in the laboratory. By culturing a highly sensitive MM cell line, AMO1, in gradually escalating doses of a MCL1 inhibitor, we were able to generate resistant pools of these cells. Interestingly, we found marked amplification of the multidrug resistance protein 1 (MDR1) gene in 3/4 generated resistant pools. We conducted a number of studies which validated MDR1 amplification as a potential mechanism of resistance to this class of MCL1 inhibitors. Firstly, ectopic overexpression of MDR1 in multiple hematopoietic cell lines conferred resistance. Secondly, this resistance is reversed by co-treatment with an advanced MDR1 inhibitor. Finally, we could restore sensitivity to this MCL1 inhibitor when MDR1 function was blocked in the resistant AMO1 pools with MDR1 amplification. Overall, our data provide strong evidence that MDR1 amplification could adversely impact this MCL1 inhibitor activity. We are also testing if other BH3 mimetics are substrates of MDR1. These studies are important because MDR1 amplification is a common mechanism that underpins resistance to multiple anti-cancer agents, both conventional and targeted.