carfilzomib

P1/2, N=60, Active, not recruiting, PETHEMA Foundation | Recruiting --> Active, not recruiting

The combination of the proteasome inhibitor carfilzomib and Mcl1 AUTAC synergistically promoted cell death in both in vitro models, including wild-type and proteasome inhibitor-resistant multiple myeloma and lung cancer cells, and in mouse tumor xenografts. Thus, our work offers a novel strategy for enhancing proteasome inhibitor efficacy by exploiting the adaptive autophagy response. More broadly, our study establishes a framework for amplifying lysosome-mediated targeted protein degradation, with potential applications in cancer therapeutics and beyond.

P1, N=25, Recruiting, National Institute of Allergy and Infectious Diseases (NIAID) | Not yet recruiting --> Recruiting | Phase classification: P2 --> P1

P1, N=166, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Apr 2027 --> Oct 2027

P2/3, N=153, Not yet recruiting, AstraZeneca AB

P2, N=41, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2026 --> Jul 2027 | Trial primary completion date: Jul 2026 --> Jul 2027

P1/2, N=300, Active, not recruiting, Karyopharm Therapeutics Inc | Recruiting --> Active, not recruiting

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.

A secondary objective was to assess whether mRNA expression levels of the endoplasmic reticulum (ER) stress sensors X-box-binding protein 1 (uXBP1) and activating transcription factor 6 (ATF6), and the chaperone-mediated autophagy marker Lysosomal-Associated Membrane Protein 2 (LAMP2A) by droplet digital PCR (ddPCR), were associated with resistance to the second-generation proteasome inhibitor (PI) carfilzomib (Cfz)...Samples were obtained as part of standard clinical care and/or during treatment with Bortezomib (Btz) or Cfz...Cfz adaptation was associated with reduced levels of uXBP1 and LAMP2A mRNA in MM cell lines. Future prospective studies evaluating the clinical utility of ER stress and chaperone-mediated autophagy associated transcripts in CPCs as predictors of resistance to PI are warranted.

P2/3, N=38, Not yet recruiting, AstraZeneca AB

P2, N=53, Active, not recruiting, Oslo University Hospital | Completed --> Active, not recruiting

P2, N=118, Active, not recruiting, Sanofi | N=55 --> 118