RNA-seq in TKI-resistant NSCLC cells
Non–small cell lung cancer (NSCLC) is the most prevalent and lethal form of lung cancer. Although EGFR–tyrosine kinase inhibitors (TKIs) have shown efficacy in patients with EGFR mutations, acquired resistance remains a major clinical challenge. While various resistance mechanisms have been identified at the upstream signaling level, many lead to the activation of downstream effectors such as YAP1. Through transcriptomic profiling of EGFR-TKI–resistant NSCLC cells, we identified upregulation of Wnt5 which leads to the activation of YAP1. Elevated level of Wnt5 was confirmed in cultured media, and Wnt5 containing media induced the expression of FAM188B as well as YAP1. Notably, YAP1 expression was abolished by FAM188B knockdown and alveolar development was markedly impaired in FAM188B knockout mice. Chromatin immunoprecipitation and dual-luciferase assays revealed that FAM188B directly binds to the YAP1 promoter region and activates its transcription. Furthermore, protein immunoprecipitation revealed FAM188B binds to RNA polymerase II associated factor components. These findings identify FAM188B as a novel transcriptional activator of YAP1 and suggest it as a potential therapeutic target for overcoming EGFR-TKI resistance in NSCLC.