Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway [scRNASeq]

Eradicating tumor dormancy that develops following oncogene-targeted therapy, including after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer (NSCLC), is an attractive therapeutic strategy but the mechanisms governing the establishment of tumor dormancy are poorly understood. We observe that blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state, characterized by extensive epigenetic remodeling and high YAP/TEAD activity. YAP/TEAD trigger an epithelial-to-mesenchymal transition (EMT) program and engage the EMT transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP or TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK induced apoptosis. Thus, YAP activation can promote the survival of EGFR-mutant NSCLC cells in the chronic absence of EGFR signaling. Eradicating this population enhances the efficacy of targeted therapies which could ultimately lead to prolonged treatment responses in cancer patients. Overall design: PC-9 EGFR-mutant NSCLC cells were treated in vitro and in vivo with EGFR-inhibitor osimertinib and MEK inhibitor trametinib until minimal residual disease-state, followed by single-cell RNA-sequencing. In vitro, the cells were treated for three weeks, followed sample preparation for single-cell RNA-seq. Control cells were treated with DMSO for 2 days. PC-9 In vivo tumors (3 mice / group) were treated with either single-agent osimertinib or with the combination of osimertinib and trametinib for three weeks, followed sample preparation for single-cell RNA-seq. Control tumors were treated with vehicle for three weeks.