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- Title
Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia.
- Authors
Khalaf, Ahmed; de Beauchamp, Lucie; Kalkman, Eric; Rattigan, Kevin; Himonas, Ekaterini; Jones, Joe; James, Daniel; Shokry, Engy Shokry Abd; Scott, Mary T.; Dunn, Karen; Tardito, Saverio; Copland, Mhairi; Sumpton, David; Shanks, Emma; Helgason, G. Vignir
- Abstract
In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)–approved voltage-gated Ca2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca2+ channels in CML LSCs (CD34+CD38−) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca2+ uptake leads to ER and mitochondrial Ca2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients. Editor's summary: Patients with chronic myeloid leukemia (CML) often relapse after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, because of persistent leukemic stem cells (LSCs). To target LSCs and overcome disease relapse, Khalaf et al. evaluated LSC reliance on mitochondrial respiration and oxidative phosphorylation (OXPHOS). They performed a screen in vitro to identify lomerizine, an FDA-approved voltage-gated calcium channel blocker as able to inhibit mitochondrial metabolism and sensitize CML LSCs to imatinib treatment. Combination in vivo extended survival of mouse models suggesting its potential for the treatment of patients with this disease. —Dorothy Hallberg
- Subjects
UNITED States. Food &; Drug Administration; CHRONIC myeloid leukemia; DRUG repositioning; DASATINIB; MYELOID leukemia; PROTEIN-tyrosine kinase inhibitors; MITOCHONDRIA; NILOTINIB
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 751, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adi5336