TOP2A knockdown resensitizes carfilzomib-resistant HMCLs to carfilzomib

e68 homeostasis in MM cells. In particular, we identified p62 as an essential component of an autophagic reserve that not only synergizes with the UPS to maintain proteostasis, but also mediates a plastic adaptive response to PIs. Altogether, these data integrate autophagy into our previously established proteasome load-versuscapacity model of PI responsiveness, and reveal p62 aggregation as a faithful marker of defective proteostasis, defining a novel prognostic and therapeutic framework for MM.