Single-cell transcriptomics of NRAS-mutated melanoma transitioning to drug resistance reveals P2RX7 as an indicator of early drug response

  • Cell Rep. 2023 Jun 27;42(7):112696. doi: 10.1016/j.celrep.2023.112696.
Tijana Randic  1 ,  Stefano Magni  2 ,  Demetra Philippidou  1 ,  Christiane Margue  1 ,  Kamil Grzyb  2 ,  Jasmin Renate Preis  1 ,  Joanna Patrycja Wroblewska  1 ,  Petr V Nazarov  3 ,  Michel Mittelbronn  4 ,  Katrin B M Frauenknecht  5 ,  Alexander Skupin  6 ,  Stephanie Kreis  7
Affiliations
  • 1. Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg.
  • 2. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg.
  • 3. 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.
  • 4. Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg; Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, 6A, Rue Nicolas-Ernest Barblé, 1210 Luxembourg, Luxembourg; National Center of Pathology (NCP), Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg.
  • 5. National Center of Pathology (NCP), Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg; Luxembourg Center of Neuropathology (LCNP), Dudelange, Luxembourg.
  • 6. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg; Department of Cancer Research (DoCR), Luxembourg Institute of Health (LIH), Luxembourg, 6A, Rue Nicolas-Ernest Barblé, 1210 Luxembourg, Luxembourg; Department of Neuroscience, University of California San Diego, 9500 Gillman Drive, La Jolla, CA 92093, USA.
  • 7. Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 6, Avenue du Swing, 4367 Belvaux, Luxembourg. Electronic address: [email protected].
PMID: 37379213 DOI: 10.1016/j.celrep.2023.112696
Abstract

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.

Keywords
CP: Cancer; MEK/CDK4/6 co-inhibition; NRAS-mutant melanoma; P2RX7; drug resistance; single-cell RNA-sequencing.
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