TY - JOUR
T1 - Single-cell transcriptomics of NRAS-mutated melanoma transitioning to drug resistance reveals P2RX7 as an indicator of early drug response
AU - Randic, Tijana
AU - Magni, Stefano
AU - Philippidou, Demetra
AU - Margue, Christiane
AU - Grzyb, Kamil
AU - Preis, Jasmin Renate
AU - Wroblewska, Joanna Patrycja
AU - Nazarov, Petr V.
AU - Mittelbronn, Michel
AU - Frauenknecht, Katrin B.M.
AU - Skupin, Alexander
AU - Kreis, Stephanie
N1 - Funding Information:
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.
Publisher Copyright:
© 2023 University of Luxembourg
PY - 2023/7/25
Y1 - 2023/7/25
N2 - 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.
AB - 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.
KW - CP: Cancer
KW - drug resistance
KW - MEK/CDK4/6 co-inhibition
KW - NRAS-mutant melanoma
KW - P2RX7
KW - single-cell RNA-sequencing
UR - https://www.scopus.com/pages/publications/85163502753
UR - https://pubmed.ncbi.nlm.nih.gov/37379213
U2 - 10.1016/j.celrep.2023.112696
DO - 10.1016/j.celrep.2023.112696
M3 - Article
C2 - 37379213
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 7
M1 - 112696
ER -