Related Experiment Video
Updated: May 5, 2026
Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Turning adaptive resistance into vulnerability: AUTAC-Mediated degradation of Mcl1
Ahmed M Elshazly1,2,3, Senthil K Radhakrishnan1,4
1Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA.
Abstract:
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.
Insights
Proteasome inhibitors are limited by adaptive stress responses. A novel Mcl1-targeting therapy combined with proteasome inhibition leverages the transcription factor NRF1 to enhance lysosomal degradation, overcoming resistance in multiple myeloma.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Stress Response
Background:
- Proteasome inhibition is a primary treatment for multiple myeloma but faces resistance.
- Adaptive stress responses, mediated by transcription factor NRF1, promote tumor cell survival.
- Mcl1 is a key protein driving resistance to proteasome inhibitors.
Purpose of the Study:
- To develop and evaluate a novel Mcl1-targeting autophagy-targeting chimera (AUTAC) for overcoming proteasome inhibitor resistance.
- To investigate the role of NRF1 in coupling proteotoxic stress to lysosomal degradation.
- To assess the synergistic potential of combining AUTAC with proteasome inhibitors.
Main Methods:
- Development of a first-in-class Mcl1-targeting AUTAC.
- Utilizing K63-linked ubiquitination by TRAF6 and UBC13 for Mcl1 degradation via p62/SQSTM1.
- Testing the combination therapy in multiple myeloma and lung cancer models, including xenografts.
- Assessing AUTAC activity in NRF1-deficient cells.
Main Results:
- The AUTAC selectively degrades Mcl1 through the lysosomal pathway.
- Proteasome inhibitor carfilzomib significantly potentiates AUTAC activity.
- NRF1 is essential for this potentiation, acting as a licensing factor.
- The combination therapy demonstrated synergistic tumor cell death and suppressed tumor growth in vivo.
Conclusions:
- NRF1 couples proteotoxic stress to enhanced lysosomal degradation, enabling a novel therapeutic strategy.
- Targeting Mcl1 with AUTAC in combination with proteasome inhibitors overcomes resistance mechanisms.
- This approach reframes autophagy as an inducible degradation capacity that can be redirected to eliminate oncogenic factors.
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