Cell plasticity, the ability of cells to change their phenotype, is regulated at transcriptional and epigenetic level and plays a pivotal role in enabling cancer cell to adapt and resist to therapy. By reprogramming their transcriptome and epigenome, tumour cells can adapt to therapeutic pressure by entering a pseudo-dormant “drug-tolerant” state (DTC for “drug-tolerant cells”). Over time, some DTC can acquire genetic and non-genetic resistances, leading to tumour relapse. However, the molecular mechanisms underlying epigenetic-mediated plasticity in adaptive response to treatment are unclear. R-loops, nucleic acid structures consisting of an RNA/DNA hybrid and a single-stranded DNA, are emerging as transcriptional and epigenetic regulators able to participate to cell identity. This research proposal aims to investigate the role of R-loops in driving cell plasticity in response to anticancer therapy, leading to treatment resistance. For this, we will use EGFR tyrosine kinase inhibitors in EGFR-mutated lung cancer cells as a well-established model of adaptive response to therapy. In this context, we will identify the transcriptional and epigenetic changes depending on R-loops, the molecular mechanisms through which R-loops trigger these changes and how they translate into phenotypic plasticity at the single-cell level and genome-wide. Addressing these questions will advance our mechanistic understanding of cell plasticity in adaptive response to anticancer treatments paving the way for the development of therapeutic strategies aimed at preventing disease relapse.