Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway [YAP1 KO vs CTRL]

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 and HCC4006 CTRL and YAP1 KO cells were plated into 10 cm dishes at 15 x 104 cells / cm2 in triplicate. The next day, the cells were treated with DMSO or with the combination of 100 nM osimertinib and 30 nM trametinib (OT). After 24 hours, the cells were lysed into TRIzol and RNA extraction was performed according to the manufacturer's protocol