Turning adaptive resistance into vulnerability: AUTAC-mediated degradation of Mcl1

Proteasome inhibition remains the frontline therapy in multiple myeloma, yet its efficacy is attenuated by adaptive stress responses. Central to these is the transcription factor NRF1, which transcriptionally upregulates proteasome subunits and components of the autophagy-lysosomal machinery, restoring proteostasis and sustaining tumor cell survival. The anti-apoptotic protein Mcl1 has independently emerged as a dominant mediator of resistance to proteasome inhibitors. In our recent work, we report a first-in-class Mcl1-targeting autophagy-targeting chimera (AUTAC) that selectively degrades Mcl1 via the lysosomal pathway through K63-linked ubiquitination by TRAF6 and UBC13, and recognition by the cargo receptor p62/SQSTM1. Proteasome inhibition with carfilzomib markedly potentiates AUTAC activity, and this potentiation is abolished in NRF1-deficient cells, establishing NRF1 as the licensing factor that couples proteotoxic stress to enhanced lysosomal targeted protein degradation. The combination produces synergistic tumor cell death across proteasome inhibitor-sensitive and resistant multiple myeloma and lung cancer models in vitro and significantly suppresses tumor growth in a U266B1 multiple myeloma xenograft model. These findings reframe cytoprotective autophagy not as a resistance liability to be inhibited, but as an inducible degradation capacity that can be redirected to eliminate oncogenic survival factors, suggesting a generalizable strategy for amplifying lysosomal targeted protein degradation through controlled proteostasis stress.