Nelfinavir overcomes proteasome inhibitor resistance in multiple myeloma by modulating lipid bilayer composition and fluidity

ABSTRACT: Nelfinavir has broad anti-cancer activity precilincally as a single agent and in combination. Clinically, it is particularly effective in the therapy of proteasome inhibitor-refractory multiple myeloma. The broad anti-cancer mechanism of action of nelfinavir implies that it may interfere with very fundamental aspects of cancer cell biology. We combined proteome-wide affinity-purification with genome-wide CRISPR/Cas9-based screening to identify protein partners interacting with nelfinavir alongside with candidate genetic contributors affecting nelfinavir cytotoxicity. We show that nelfinavir has multiple binding partners embedded in organellar lipid-rich membranes. By binding to these, nelfinavir affects the composition and fluidity of lipid-rich membranes, which subsequently disrupts downstream membrane-related processes, such as lipid metabolism, glucose processing, mitochondrial respiration, vesicular transport and ABCB1-mediated drug efflux. Targeting membrane fluidity by FDA-approved drug nelfinavir is a potent mechanism to achieve anti-cancer activity and is in particular suitable for the treatment of proteasome inhibitor-refractory multiple myeloma.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Suspension Culture, Epithelial Cell, Cell Culture

DISEASE(S): Lymphoma,Breast Cancer

SUBMITTER: Bogdan Florea  

LAB HEAD: Lenka Besse

PROVIDER: PXD023260 | Pride | 2021-11-02

REPOSITORIES: Pride