{"doi":"10.1038/s41375-020-0962-2","title":"The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma","abstract":"Multiple myeloma (MM) is a plasma cell malignancy that is often driven by chromosomal translocations. In particular, patients with t(4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated that t(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 in t(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 that t(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 in t(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 in t(4;14)-positive cells and potentiated the anti-tumor activity of bortezomib in vivo. Our data implicate the t(4;14) translocation as a biomarker of statin sensitivity and warrant further clinical evaluation of a statin in combination with bortezomib for the treatment of t(4;14)-positive disease.","journal":"Leukemia","year":2020,"id":95411,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":473884,"name":"Petr Smirnov","orcid":"0000-0001-9395-8450","position":1,"is_corresponding":false},{"id":473885,"name":"Zhihua Li","orcid":"0000-0003-4820-4603","position":2,"is_corresponding":false},{"id":474449,"name":"Emily Branchard","orcid":null,"position":3,"is_corresponding":false},{"id":473886,"name":"Jenna E. van Leeuwen","orcid":"0000-0002-4744-2960","position":4,"is_corresponding":false},{"id":237415,"name":"Jonathan D. Licht","orcid":"0000-0002-3942-1369","position":5,"is_corresponding":false},{"id":12606,"name":"Benjamin Haibe‐Kains","orcid":"0000-0002-7684-0079","position":6,"is_corresponding":false},{"id":356210,"name":"David W. Andrews","orcid":"0000-0002-9266-7157","position":7,"is_corresponding":false},{"id":25413,"name":"Jonathan J. Keats","orcid":"0000-0003-4375-7399","position":8,"is_corresponding":false},{"id":25434,"name":"Trevor J. Pugh","orcid":"0000-0002-8073-5888","position":9,"is_corresponding":false},{"id":25438,"name":"Suzanne Trudel","orcid":"0000-0001-7952-6352","position":10,"is_corresponding":false},{"id":473887,"name":"Linda Z. Penn","orcid":"0000-0001-8133-5459","position":11,"is_corresponding":false},{"id":473883,"name":"Joseph Longo","orcid":"0000-0002-9580-5105","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T22:33:30.364261Z","pmid":"32665698","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}