Single-cell transcriptomics of NRAS-mutated melanoma transitioning to drug resistance reveals P2RX7 as an indicator of early drug response
Tijana Randic, Stefano Magni, Demetra Philippidou, Christiane Margue, Kamil Grzyb, Jasmin Renate Preis, Joanna Wróblewska, Petr V. Nazarov, Michel Mittelbronn, Katrin Frauenknecht, Alexander Skupin, Stephanie Kreis
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.