2. Academic Validation
  3. Realigned transsulfuration drives BRAF-V600E-targeted therapy resistance in melanoma

Realigned transsulfuration drives BRAF-V600E-targeted therapy resistance in melanoma

  • Cell Metab. 2025 Feb 28:S1550-4131(25)00021-X. doi: 10.1016/j.cmet.2025.01.021.
Klaudia Borbényi-Galambos 1,  Katalin Erdélyi 2,  Tamás Ditrói 2,  Eszter Petra Jurányi 3,  Noémi Szántó 2,  Réka Szatmári 4,  Ágnes Czikora 2,  Edward E Schmidt 5,  Dorottya Garai 1,  Mihály Cserepes 6,  Gabriella Liszkay 7,  Erika Tóth 8,  József Tóvári 6,  Péter Nagy 9
Affiliations

Affiliations

  • 1 Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hajdú-Bihar County, 4032, Hungary.
  • 2 Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary.
  • 3 Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Semmelweis University Doctoral School, Semmelweis University, Budapest, 1094, Hungary.
  • 4 Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hajdú-Bihar County, 4032, Hungary; Chemistry Coordinating Institute, University of Debrecen, Debrecen, Hajdú-Bihar County, 4012, Hungary.
  • 5 Department of Anatomy and Histology, HUN-REN-UVMB Laboratory of Redox Biology, University of Veterinary Medicine, Budapest, 1078, Hungary; Department of Microbiology and Cell Biology, Montana State University, Bozeman, Montana, 59717, United States of America.
  • 6 Department of Experimental Pharmacology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary.
  • 7 Department of Dermatology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary.
  • 8 Department of Surgical and Molecular Pathology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary.
  • 9 Department of Molecular Immunology and Toxicology and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, 1122, Hungary; Chemistry Coordinating Institute, University of Debrecen, Debrecen, Hajdú-Bihar County, 4012, Hungary; Department of Anatomy and Histology, HUN-REN-UVMB Laboratory of Redox Biology, University of Veterinary Medicine, Budapest, 1078, Hungary. Electronic address: peter.nagy@oncol.hu.
PMID: 40037361 DOI: 10.1016/j.cmet.2025.01.021
Abstract

BRaf V600E-inhibition effectively treats melanoma, but acquired resistance rapidly develops. Protein expression profiles, mitochondrial energetics, metabolomics and fluxomics data in cell line, xenograft, and patient-derived xenograft systems revealed that concerted reprogramming of metabolic pathways (including glutaminolysis, glycolysis, TCA cycle, electron transport chain [ETC], and transsulfuration), along with an immediate cytoprotective response to drug-induced oxidative stress, underpins drug-tolerant persister Cancer cell survival. Realignment of cysteine (Cys) metabolism, in particular an immediate upregulation of cystathionine-γ-lyase (CSE), was vital in persister cells. The oxidative cellular environment, drug-induced elevated cystine uptake and oxidative Cys catabolism, increased intracellular cystine/Cys ratios, thereby favoring cystine as a CSE substrate. This produces persulfides and hydrogen sulfide to protect protein thiols and support elevated energy demand in persister cells. Combining BRaf V600E inhibitors with CSE inhibitors effectively diminished proliferative relapse in culture models and increased progression-free survival of xenografted mice. This, together with induced CSE expression in patient samples under BRAF-V600E-inhibition, reveals an approach to increase BRAF-V600E-targeted therapeutic efficacy.

Keywords

BRAF V600E targeted therapy resistance; cystathionine γ-lyase; cysteine metabolism; fluxomics of metabolic reprogramming; hydrogen sulfide; melanoma; persister cells; persulfide; redox regulation; transsulfuration.

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