Integrative Transcriptomic Analysis Identifies Emetine as A Promising Drug Candidate for Overcoming Acquired Resistance to ALK Inhibitors in Lung Cancer
Anaplastic lymphoma kinase (ALK) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKi invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta-analysis of transcriptome data from various cell models of acquired resistance to ALKi. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi-resistant cells. We demonstrated that this drug exhibited effectiveness in inhibiting the growth of ALKi-resistant cells, and further elucidated its mode of action through drug-induced RNA-seq data. Our transcriptome-guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy. Overall design: To investigate whether the inhibitory effects of emetine on H3122-LR cell growth are associated with the resistant signature, we generated RNA-seq data of H3122-LR cells treated with DMSO or emetine.