The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ATAC-seq]

Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. Whilst patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq, ChIP-seq, and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic opportunities. Overall design: The NSCLC EGFR mutant cell lines (PC9, NCI-H1975, HCC827, and HCC2935) were treated with 500 nM of osimertinib for 24 days (osimertinib DTPs) or treated with 500 nM of osimertinib for 21 days followed by 150 nM of AZD5153 for 3 days (osimertinib DTP AZD5153 sequential combination). In parallel, parental cell lines were grown in drug-free media for 21 days then treated with vehicle DMSO control for 3 days (DMSO control). As an additional control, PC9 and H1975 cell lines were grown in drug-free media for 21 days then treated with 150 nM of AZD5153 for 3 days (AZD5153 monotherapy). Experiment was done using biological triplicates. There are 42 total ATAC-seq samples.