Targeting the mevalonate pathway sensitizes multiple myeloma cells to bortezomib through induction of mitochondrial metabolic disruption.

BACKGROUND

Multiple myeloma (MM) remains an incurable hematologic malignancy with bortezomib resistance representing a major therapeutic challenge. The mevalonate (MVA) pathway, a crucial metabolic cascade involved in cholesterol synthesis, has emerged as a potential target for cancer therapy.

METHODS

In this study, we first investigated the correlations between the MVA pathway and MM progression. Leveraging public databases, transcriptome sequencing, mass cytometry, as well as in vitro and in vivo experimental models, we further systematically evaluated the therapeutic efficacy and underlying mechanisms of statins, a class of clinically available MVA pathway inhibitors, for the treatment of MM.

RESULTS

Using microarray and sequencing datasets, we found that the MVA pathway is dysregulated in MM and correlated with poor prognosis, as core genes in this pathway were significantly dysregulated in MM patients. Statins directly inhibit MM cell viability, induce apoptosis, and up-regulate apoptosis-associated proteins. These effects of statins are associated with the activation of the ERK pathway. They also induce dysregulation of metabolism, oxidative stress, and autophagy in MM cells. Moreover, the combination of statins and bortezomib exerts a synergistic anti-MM effect both in vitro and in vivo.

CONCLUSIONS

Our preclinical data suggest that the MVA pathway can serve as a therapeutic target for MM and the combination of statins, widely used and safe drugs in the clinic, with bortezomib offers a promising strategy to overcome bortezomib resistance and improve therapeutic outcomes for MM patients.