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

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. PC-9, HCC827 and HCC4006 cells were plated at 15 x 104 cells / cm2 into 10 cm plates (DMSO treated control cells) or into 15 cm plates (dormant cells) in duplicate. The next day, cells were treated either with DMSO or with the combination of 100 nM osimertinib and 30nM trametinib. DMSO-treated control cells were harvested 24h later, and the dormant cells after 2 weeks of treatment. At these timepoints, cells were lysed into TRIzol and RNA extraction was performed according to the manufacturer’s protocol.