The Mevalonate Pathway Is An Actionable Vulnerability Oft(4;14)-Positive Multiple Myeloma

Multiple myeloma (MM) is a plasma cell malignancy that is often driven by chromosomal translocations. In particular, patients witht(4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated thatt(4;14)-positive cells are highly dependent on the mevalonate (MVA) pathway for survival. Moreover, we showed that this metabolic vulnerability is immediately actionable, as inhibiting the MVA pathway with a statin preferentially induced apoptosis int(4;14)-positive cells. In response to statin treatment,t(4;14)-positive cells activated the integrated stress response (ISR), which was augmented by co-treatment with bortezomib, a proteasome inhibitor. We identified thatt(4;14)-positive cells depend on the MVA pathway for the synthesis of geranylgeranyl pyrophosphate (GGPP), as exogenous GGPP fully rescued statin-induced ISR activation and apoptosis. Inhibiting protein geranylgeranylation similarly induced the ISR int(4;14)-positive cells, suggesting that this subtype of MM depends on GGPP, at least in part, for protein geranylgeranylation. Notably, fluvastatin treatment synergized with bortezomib to induce apoptosis int(4;14)-positive cells and potentiated the anti-tumor activity of bortezomib in vivo. Our data implicate thet(4;14) translocation as a biomarker of statin sensitivity and warrant further clinical evaluation of a statin in combination with bortezomib for the treatment oft(4;14)-positive disease.