Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice
Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies have analyzed the relationship between...
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MDPI AG
2025-06-01
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| author | Pratima Nangia-Makker Madison Ahrens Neeraja Purandare Siddhesh Aras Jing Li Katherine Gurdziel Hyejeong Jang Seongho Kim Malathy P Shekhar |
| author_facet | Pratima Nangia-Makker Madison Ahrens Neeraja Purandare Siddhesh Aras Jing Li Katherine Gurdziel Hyejeong Jang Seongho Kim Malathy P Shekhar |
| author_sort | Pratima Nangia-Makker |
| collection | DOAJ |
| description | Melanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies have analyzed the relationship between vemurafenib tolerance levels and metabolic plasticity. To determine how vemurafenib endurance levels drive metabolic plasticity, we developed isogenic BRAFV600E VemR melanoma models with variant vemurafenib tolerances and performed an integrative analysis of metabolomic and transcriptome alterations using metabolome, Mitoplate-S1, Seahorse, and RNA-seq assays. Regardless of drug tolerance differences, both VemR models display resistance to MEK inhibitor and sensitivity to Wnt/β-catenin inhibitor, ICG-001. β-catenin, MITF, and ABCB5 levels are upregulated in both VemR models, and ICG-001 treatment restored vemurafenib sensitivity with reductions in MITF, ABCB5, phospho-ERK1/2, and mitochondrial respiration. Whereas β-catenin signaling induced TCA cycle and OXPHOS in highly drug tolerant A2058VemR cells, it activated pentose phosphate pathway in M14VemR cells with low vemurafenib tolerance, both of which are inhibited by ICG-001. These data implicate an important role for Wnt/β-catenin signaling in VemR-induced metabolic plasticity. Our data demonstrate that drug tolerance thresholds play a direct role in driving metabolic shifts towards specific routes, thus providing a new basis for delineating VemR melanomas for metabolism-targeting therapies. |
| format | Article |
| id | doaj-art-cf94aa8a050a4c079890945242b8a4f6 |
| institution | OA Journals |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-cf94aa8a050a4c079890945242b8a4f62025-08-20T02:24:42ZengMDPI AGCells2073-44092025-06-01141292310.3390/cells14120923Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway ChoicePratima Nangia-Makker0Madison Ahrens1Neeraja Purandare2Siddhesh Aras3Jing Li4Katherine Gurdziel5Hyejeong Jang6Seongho Kim7Malathy P Shekhar8Karmanos Cancer Institute, 421 E. Canfield Avenue, Detroit, MI 48201, USAKarmanos Cancer Institute, 421 E. Canfield Avenue, Detroit, MI 48201, USACenter for Molecular Medicine and Genetics, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201, USADepartment of Oncology, Wayne State University School of Medicine, 421 E. Canfield Avenue, Detroit, MI 48201, USAKarmanos Cancer Institute, 421 E. Canfield Avenue, Detroit, MI 48201, USAInstitute of Environmental Health Sciences, Wayne State University, Detroit, MI 48202, USAKarmanos Cancer Institute, 421 E. Canfield Avenue, Detroit, MI 48201, USAKarmanos Cancer Institute, 421 E. Canfield Avenue, Detroit, MI 48201, USAKarmanos Cancer Institute, 421 E. Canfield Avenue, Detroit, MI 48201, USAMelanomas quickly acquire resistance to vemurafenib, an important therapeutic for BRAFV600 mutant melanomas. Although combating vemurafenib resistance (VemR) to counter mitochondrial metabolic shift using mitochondria-targeting therapies has promise, no studies have analyzed the relationship between vemurafenib tolerance levels and metabolic plasticity. To determine how vemurafenib endurance levels drive metabolic plasticity, we developed isogenic BRAFV600E VemR melanoma models with variant vemurafenib tolerances and performed an integrative analysis of metabolomic and transcriptome alterations using metabolome, Mitoplate-S1, Seahorse, and RNA-seq assays. Regardless of drug tolerance differences, both VemR models display resistance to MEK inhibitor and sensitivity to Wnt/β-catenin inhibitor, ICG-001. β-catenin, MITF, and ABCB5 levels are upregulated in both VemR models, and ICG-001 treatment restored vemurafenib sensitivity with reductions in MITF, ABCB5, phospho-ERK1/2, and mitochondrial respiration. Whereas β-catenin signaling induced TCA cycle and OXPHOS in highly drug tolerant A2058VemR cells, it activated pentose phosphate pathway in M14VemR cells with low vemurafenib tolerance, both of which are inhibited by ICG-001. These data implicate an important role for Wnt/β-catenin signaling in VemR-induced metabolic plasticity. Our data demonstrate that drug tolerance thresholds play a direct role in driving metabolic shifts towards specific routes, thus providing a new basis for delineating VemR melanomas for metabolism-targeting therapies.https://www.mdpi.com/2073-4409/14/12/923melanomaBRAFadaptive resistanceRNA-seqmetabolomeWnt signaling |
| spellingShingle | Pratima Nangia-Makker Madison Ahrens Neeraja Purandare Siddhesh Aras Jing Li Katherine Gurdziel Hyejeong Jang Seongho Kim Malathy P Shekhar Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice Cells melanoma BRAF adaptive resistance RNA-seq metabolome Wnt signaling |
| title | Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice |
| title_full | Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice |
| title_fullStr | Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice |
| title_full_unstemmed | Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice |
| title_short | Inter-Relationship Between Melanoma Vemurafenib Tolerance Thresholds and Metabolic Pathway Choice |
| title_sort | inter relationship between melanoma vemurafenib tolerance thresholds and metabolic pathway choice |
| topic | melanoma BRAF adaptive resistance RNA-seq metabolome Wnt signaling |
| url | https://www.mdpi.com/2073-4409/14/12/923 |
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