E-Poster Presentation 33rd Lorne Cancer Conference 2021

Role of the multi-drug resistance efflux pump MDR1 in conferring resistance to the BH3- mimetic compounds (#121)

Farima Moghaddaskho 1 2 , Yuan Yao 1 3 , Christoffer Flensburg 1 2 , Jia-nan Gong 1 2 , Christine A White 1 2 , Ian J Majewski 1 2 , Andrew W Roberts 1 2 4 5 6 , David CS Huang 1 2
  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia
  3. School of Medicine, Tsinghua University, Beijing, China
  4. Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
  5. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia

Impaired apoptotic cell death is implicated in the pathogenesis of many blood cancers. In chronic lymphocytic leukaemia, the pro-survival protein BCL2 is highly expressed and inhibiting BCL2 with a selective small molecule inhibitor venetoclax has proven to be highly effective. In other haematological malignancies such as multiple myeloma (MM), a pro-survival relative of BCL2, MCL1, plays a critical role. Venetoclax and other small molecules targeting the pro-survival BCL2 proteins are referred to as BH3-mimetic compounds. As these drugs enter clinical trials for diseases such as MM, we attempted to understand from laboratory studies why they might fail.

To do this for the MCL1 inhibitor (MCL1i) S63845, resistant sub-clones of a sensitive myeloma cell line were selected by growing them in escalating doses of the drug. As expected, increased expression of the pro-survival proteins (BCL2, BCLxL) spared by the MCL1i was detected in some of the resistant cells. However, the prominent driver of resistance was increased expression of the multi-drug resistance protein 1 (MDR1). This was sufficient to confer resistance since cells independently engineered to overexpress MDR1 became highly resistant and a specific inhibitor of MDR1 could restore their sensitivity to S63845. Furthermore, cells known to have MDR1 amplification could be sensitised to S63845 by co-inhibiting MDR1.

We next tested if the action of other chemical classes of BH3-mimetics that target MCL1 are also impacted by MDR1 overactivity. Unlike S63845 and its chemical analogs, the action of AMG-176, a distinct MCL1i, was not affected by overexpressing MDR1. Amongst the other BH3-mimetics we tested, the action of the BCL2 inhibitor S55746 was also compromised by MDR1 overexpression.

Taken together, our findings suggest that MDR1 overactivity could potentially pose a barrier to the clinical efficacy of distinct classes of BH3-mimetics that target MCL1 (S63845 and its relatives) and BCL2 (S55746 and compounds of the same class). We conclude that other inhibitors of MCL1 or BCL2 should be considered in cancers with MDR1 overexpression.