MYC plus class IIa HDAC inhibiton potentiates mitochondrial dysfunction in non-small cell lung cancer [ATAC-seq]

To evaluate potential therapeutic benefits from dual targeting of MYC and class IIa HDACs, we assessed the treatment efficacy of MYCi plus class IIa HDACi across 18 NSCLC cell lines, 10 of which demonstrated substantial reduction of cell viability upon combination treatment. RNA sequencing on treated cell lines identified large-scale transcriptional shifts facilitated by combination treatment, including suppression of MYC, cell cycle, and mitochondrial pathways. ATAC-sequencing showed chromatin structure changes in genomic regions involved in cell cycle progression and inflammatory signaling. Furthermore, G1/S arrest and elevated mitochondrial ROS levels in combination drug-treated cells were confirmed using flow cytometry. Concordant with the role of MYC as a key cell cycle regulator, MYC protein levels were decreased in the combination treatment group as compared to the vehicle or mono-treatment groups. In summary, we define here a novel drug paradigm combining MYC and class IIa HDAC inhibitors, which potentiates anti-tumor efficacy in NSCLC via MYC depletion and oxidative stress. Overall design: To identify drug treatment-induced chromatin structure changes, two NSCLC cell lines (H460 and H838) were treated with either DMSO, MYCi975, TMP195 or combination for 24 hours and subjected to ATAC-seq library preparation.