CP: Cancer; MEK/CDK4/6 co-inhibition; NRAS-mutant melanoma; P2RX7; drug resistance; single-cell RNA-sequencing; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; P2RX7 protein, human; Receptors, Purinergic P2X7; NRAS protein, human; Membrane Proteins; GTP Phosphohydrolases; Humans; Protein Kinase Inhibitors/pharmacology; Drug Resistance, Neoplasm/genetics; Cell Line, Tumor; Mutation/genetics; Proto-Oncogene Proteins B-raf/genetics; Receptors, Purinergic P2X7/metabolism; Membrane Proteins/metabolism; GTP Phosphohydrolases/genetics; GTP Phosphohydrolases/metabolism; Transcriptome; Melanoma/drug therapy; Melanoma/genetics; Melanoma/metabolism; Drug Resistance, Neoplasm; Melanoma; Mutation; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology
Abstract :
[en] Treatment options for patients with NRAS-mutant melanoma are limited and lack an efficient targeted drug combination that significantly increases overall and progression-free survival. In addition, targeted therapy success is hampered by the inevitable emergence of drug resistance. A thorough understanding of the molecular processes driving cancer cells' escape mechanisms is crucial to tailor more efficient follow-up therapies. We performed single-cell RNA sequencing of NRAS-mutant melanoma treated with MEK1/2 plus CDK4/6 inhibitors to decipher transcriptional transitions during the development of drug resistance. Cell lines resuming full proliferation (FACs [fast-adapting cells]) and cells that became senescent (SACs [slow-adapting cells]) over prolonged treatment were identified. The early drug response was characterized by transitional states involving increased ion signaling, driven by upregulation of the ATP-gated ion channel P2RX7. P2RX7 activation was associated with improved therapy responses and, in combination with targeted drugs, could contribute to the delayed onset of acquired resistance in NRAS-mutant melanoma.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
RANDIC, Tijana ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Stephanie KREIS
MAGNI, Stefano ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Imaging AI
PHILIPPIDOU, Demetra ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Margue, Christiane; Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg
PREIS, Jasmin Renate ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
WROBLEWSKA, Joanna Patrycja ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
NAZAROV, Petr ; University of Luxembourg ; Data Integration and Analysis Unit (DIA), Luxembourg Institute of Health, 1A-B, Rue Thomas Edison, 1445 Strassen, Luxembourg, Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, 6A, Rue Nicolas-Ernest Barblé, 1210 Luxembourg, Luxembourg
MITTELBRONN, Michel ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Neuropathology
FRAUENKNECHT, Katrin ; University of Luxembourg ; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg, Luxembourg Center of Neuropathology (LCNP), Dudelange, Luxembourg
SKUPIN, Alexander ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Integrative Cell Signalling
KREIS, Stephanie ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
External co-authors :
no
Language :
English
Title :
Single-cell transcriptomics of NRAS-mutated melanoma transitioning to drug resistance reveals P2RX7 as an indicator of early drug response.
We thank Prof. Dagmar Kulms (University Clinics Dresden) for sharing M20 cells with us and Dr. Elisabeth Letellier for critically reading the manuscript. We thank Vincent Gureghian for identifying senescence in MelJuso and for valuable discussions on cellular responses to drugs, Dr. Mirjana Efremova and Dr. Anthoula Gaigneaux for valuable advice on single-cell data analysis, and Dr. Vitaly Pozdeev for expert support on FACS analysis. The work by T.R. and S.M. is supported by the Luxembourg National Research Fond ( FNR ) PRIDE DTU CriTiCS (grant reference 10907093 ). M.M. is supported by an FNR PEARL P16/BM/11192868 grant. P.V.N. was supported by the Luxembourg FNR CORE grant C21/BM/15739125/ DIOMEDES.
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