Heterogeneous modulation of Bcl-2 family members and drug efflux mediate MCL-1 inhibitor resistance in multiple myeloma.

Abstract

Anti-apoptotic Bcl-2 family members recently (re)emerged as key drug targets in cancer, with a tissue and tumour specific activity profile of available BH3 mimetics. In multiple myeloma, MCL-1 was described as a major gatekeeper of apoptosis. This discovery has led to the rapid establishment of clinical trials evaluating the impact of various MCL-1 inhibitors. However, our understanding about the clinical impact and optimal use of MCL-1 inhibitors is still limited. We therefore explored mechanisms of acquired MCL-1 inhibitor resistance and optimization strategies in myeloma. Our findings indicate heterogeneous paths to resistance involving baseline Bcl-2 family alterations of pro- (BAK, BAX, BIM) and anti-apoptotic (Bcl-2, MCL-1) proteins. These manifestations depend on the BH3-profile of parental cells which guide the enhanced formation of Bcl-2:BIM and/or dynamic (i.e. treatment-induced) formation of Bcl-xL:BIM and Bcl-xL:BAK complexes. Accordingly, an unbiased high-throughput drug (n=528) screening approach highlighted alternative BH3 mimetics as top combination partners for MCL-1 inhibitors in sensitive and resistant cells (Bcl-xL>Bcl-2 inhibition), whereas established drug classes were mainly antagonistic (e.g. anti-mitotic agents). We also revealed reduced activity of MCL-1 inhibitors in the presence of stromal support as a drug-class effect which was overcome by concurrent Bcl-xL or Bcl-2 inhibition. Finally, we demonstrate heterogeneous Bcl-2 family deregulation and MCL-1 inhibitor cross-resistance in carfilzomib resistant cells, a phenomenon linked to MDR1-driven drug efflux of MCL-1 inhibitors. The implications of our findings for clinical practice underline the need for patient adapted treatment protocols, with the tracking of tumour and/or clone specific adaptations in response to MCL-1 inhibition.