bortezomib

P2, N=20, Active, not recruiting, Institute of Hematology & Blood Diseases Hospital, China | Recruiting --> Active, not recruiting

P1/2, N=72, Not yet recruiting, Northwell Health

This heterogeneity is derived from differences in the strength and duration of PERK-mediated translational inhibition, which gates downstream translation-dependent IRE1α and ATF6 transcriptional programs. Finally, in multiple myeloma, we show that bortezomib-tolerant cells depend on IRE1α activity for survival, linking UPR state to proteasome-inhibitor resistance and positioning SNUPR to guide branch-selective targeting.

To address this, we performed proteome and phosphoproteome profiling of 12 MM cell line models, comprising four parental lines (AMO-1, ARH77, L363, and RPMI8226) paired with lines that acquired resistance to bortezomib (BTZ) or carfilzomib (CFZ). Beyond known adaptations such as the overexpression of the PI target PSMB5 and the drug efflux transporter ABCB1, we identified the oxidoreductases NQO1 and NQO2 as significantly upregulated proteins under chronic proteotoxic stress across several models. Pharmacological follow up in PI resistant AMO-1 cells showed that NQO2 inhibition by imatinib fully restored CFZ sensitivity, validating NQO2 as a contributor to resistance formation in this model system.

P3, N=399, Not yet recruiting, University of Heidelberg Medical Center

P1/2, N=300, Active, not recruiting, Australasian Leukaemia & Lymphoma Group | Recruiting --> Active, not recruiting

Functionally, MAGEC2 promoted malignant proliferation and induced resistance to adriamycin and bortezomib. MAGEC2 overexpression also exacerbated bone lesions in vivo. Collectively, these findings identify MAGEC2 as both a prognostic biomarker and a promising therapeutic target in MM, and highlight its role as a multifunctional regulator of the ubiquitin system.

Here we show calcium/calmodulin-dependent protein kinase II gamma (CaMKII-γ) regulates bortezomib-resistant MM (BRMM) via AMPK-ULK1-autophagy axis. High-throughput screening identified ruxolitinib as a selective CaMKII-γ inhibitor, which reverses BRMM resistance in vitro (using U266 and KMS11 bortezomib-resistant cell lines) and in vivo (using female BALB/c nude mouse model), with efficacy comparable to genetic CaMKII-γ ablation, providing a potential therapeutic strategy for BRMM with broader implications to improve patient outcomes in the future.

CDKN3 overexpression prevented the effects of si-MYBL2 on ferroptosis and BTZ sensitivity in MM cells by interacting with the PI3K/Akt signaling pathway. In conclusion, knockdown of MYBL2 promoted ferroptosis and enhanced the BTZ sensitivity of MM cells through transcriptional regulation of CDKN3 and inactivation of the PI3K/Akt signaling pathway.

P3, N=480, Recruiting, PETHEMA Foundation | Not yet recruiting --> Recruiting

P3, N=1000, Not yet recruiting, Janssen Research & Development, LLC

This is the first study to model gastrointestinal side effects of bortezomib in rodents, implicating neuroimmune dysregulation of the vagus nerve. Our data show that the gut microbiota is not a primary driver of bortezomib side effects. However, the absence of a symptom profile in FMT mice suggests that, in GF mice, the gut microbiota beneficially modulates the host to protect against bortezomib side effects. Further studies are required to determine whether this can be harnessed to mitigate clinical complications of bortezomib.