Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

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.

People
Khalaf, Ahmed
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

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de Beauchamp, Lucie
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

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Kalkman, Eric R.
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Rattigan, Kevin M. and Zarou, Martha M. and Brabcova, Zuzana and Prasad, Bodhayan and Zerbst, Désirée and Sarnello, Daniele and Kalkman, Eric R. and Ianniciello, Angela and Scott, Mary T. and Dunn, Karen and Shokry, Engy and Sumpton, David and Copland, Mhairi and Tardito, Saverio and Vande Voorde, Johan and Mussai, Francis and Cheng, Paul and Helgason, G. Vignir (2023) Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells. EMBO Reports, 24: e56279. ISSN 1469-221X

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Rattigan, Kevin M.
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723

Rattigan, Kevin M. (2024) Mini review of metabolism in leukaemia: from complexity to the clinic. Frontiers in Hematology, 2: 1353994. ISSN 2813-3935

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Himonas, Ekaterini
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723

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Jones, Joe
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

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James, Daniel
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

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Shokry, Engy Shokry Abd
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

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Scott, Mary T.
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723

Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723

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Dunn, Karen M.
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723

Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723

See full publications list
Tardito, Saverio
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Rattigan, Kevin M. and Zarou, Martha M. and Brabcova, Zuzana and Prasad, Bodhayan and Zerbst, Désirée and Sarnello, Daniele and Kalkman, Eric R. and Ianniciello, Angela and Scott, Mary T. and Dunn, Karen and Shokry, Engy and Sumpton, David and Copland, Mhairi and Tardito, Saverio and Vande Voorde, Johan and Mussai, Francis and Cheng, Paul and Helgason, G. Vignir (2023) Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells. EMBO Reports, 24: e56279. ISSN 1469-221X

See full publications list
Copland, Mhairi
Author

Copland, Mhairi (2024) Triplet therapy for advanced BCR::ABL1 positive myeloid leukaemias. Lancet Haematology, 11 (11). e807-e808. ISSN 2352-3026

Innes, Andrew I. and Hayden, Chloe and Orovbon, Victoria and Claudiani, Simone and Fernando, Fiona and Khan, Afzal and Rees, David and Byrne, Jennifer and Gallipoli, Paolo and Francis, Sebastian and Copland, Mhairi and Horne, Gillian and Raghavan, Manoj and Arnold, Claire and Collins, Angela and Cranfield, Tanya and Cunningham, Nicholas and Danga, Akila and Forsythe, Peter and Frewin, Rebecca and Garland, Paula and Hannah, Guy and Avenoso, Daniele and Hassan, Sandra and Huntly, Brian J.P. and Husain, Jissan and Makkuni, Sudhakaran and Rothwell, Kate and Khorashad, Jamshid and Apperley, Jane F. and Milojkovic, Dragana (2024) Impact of BCR::ABL1 single nucleotide variants on asciminib efficacy. Leukemia, 38 (11). pp. 2443-2455. ISSN 0887-6924

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

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Sumpton, David
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723

See full publications list
Shanks, Emma
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Papalazarou, Vasileios and Newman, Alice C. and Huerta-Uribe, Alejandro and Legrave, Nathalie M. and Falcone, Mattia and Zhang, Tong and McGarry, Lynn and Athineos, Dimitris and Shanks, Emma and Blyth, Karen and Vousden, Karen H. and Maddocks, Oliver D. K. (2023) Phenotypic profiling of solute carriers characterises serine transport in cancer. Nature Metabolism, 5. pp. 2148-2168. ISSN 2522-5812

Papalazarou, Vasileios and Newman, Alice C. and Huerta-Uribe, Alejandro and Legrave, Nathalie M. and Falcone, Mattia and Zhang, Tong and McGarry, Lynn and Athineos, Dimitris and Shanks, Emma and Blyth, Karen and Vousden, Karen H. and Maddocks, Oliver D. K. (2023) Phenotypic profiling of solute carriers characterizes serine transport in cancer. Nature Metabolism, 5 (12). pp. 2148-2168. ISSN 2522-5812

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Helgason, G. Vignir
Author

Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir (2024) Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia. Science Translational Medicine, 16 (751): eadi5336. ISSN 1946-6234

Zarou, Martha M. and Rattigan, Kevin M. and Sarnello, Daniele and Shokry, Engy and Dawson, Amy and Ianniciello, Angela and Dunn, Karen and Copland, Mhairi and Sumpton, David and Vazquez, Alexei and Helgason, Vignir (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15: 1931. ISSN 2041-1723

Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723

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Title:
Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia
Creators:
Khalaf, Ahmed and de Beauchamp, Lucie and Kalkman, Eric and Rattigan, Kevin and Himonas, Ekaterini and Jones, Joe and James, Daniel and Shokry, Engy Shokry Abd and Scott, Mary T. and Dunn, Karen and Tardito, Saverio and Copland, Mhairi and Sumpton, David and Shanks, Emma and Helgason, Vignir
Identification Number:
10.1126/scitranslmed.adi5336
Date:
12 June 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
American Association for the Advancement of Science
Additional Information:
This work was supported by Newton-Mosharafa Fund Scholarship (awarded to A.K.). Cancer Research UK (A29754, to G.V.H.), University of Glasgow PhD Studentship (to L.B), Chief Scientist Office (CGA/18/02, to L.B and G.V.H), Blood Cancer UK (formerly Bloodwise; Ref 18006, to G.V.H), The Howat Foundation (to G.V.H.) and Friends of Paul O’Gorman Leukaemia Research Centre (o G.V.H.). Cancer Research UK (A23982) to S.T. and D.S.
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https://pub.demo35.eprints-hosting.org/id/eprint/233
Item Type:
Article
Depositing User:
Unnamed user with email ejo1f20@soton.ac.uk
Date Deposited:
11 Jun 2025 16:36
Revision:
42
Last Modified:
12 Jun 2025 11:09
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