ULK1, a novel therapeutic target to delay drug tolerance to EGFR–TKIs in an EGFR-mutant non-small cell lung cancer model

作者：Ayako Morita, Kammei Rai, Tadahiro Kuribayashi, Shuta Tomida, Tatsuya Nishi, Naofumi Hara, Go Makimoto, Kiichiro Ninomiya, Toshio Kubo, Kadoaki Ohashi, Katsuyuki Hotta, Nobuaki Ochi, Yosuke Togashi, Yoshinobu Maeda, Eiki Ichihara · 发表于：Lung Cancer · 年份：2026 · DOI：10.1016/j.lungcan.2026.109516 · 研究领域：Lung Cancer Treatments and Mutations、NF-κB Signaling Pathways、PI3K/AKT/mTOR signaling in cancer

BACKGROUND: The presence of drug-tolerant persister (DTP) cells reduces the effectiveness of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in EGFR-mutated non-small cell lung cancer (NSCLC). Although autophagy is a potential target for eliminating DTP cells, clinical trials targeting autophagy in EGFR-mutant NSCLC have been unsuccessful-likely because most trials have utilized chloroquine, non-specifically inhibiting autophagy targeting lysosomes with dose limitations. This study focused on unc-51-like autophagy activating kinase 1 (ULK1), a more specific target for autophagy inhibition, to assess whether ULK1 inhibition delays the emergence of tolerance to EGFR-tyrosine kinase inhibitors in EGFR-mutant NSCLC cells. METHODS: DTP cells were generated by treating EGFR-mutant NSCLC cell lines with osimertinib. Autophagy status and ULK1 expression were evaluated using immunofluorescence, western blotting, and quantitative real-time PCR. The effects of both pharmacological and genetic inhibition of ULK1 were examined in vitro and in vivo. RESULTS: ULK1 and LC3-II, markers of autophagy, were upregulated in DTP cells. Inhibition of ULK1, either pharmacologically or genetically, suppressed autophagy, prevented the formation of DTP cells, and enhanced the antitumor activity of osimertinib in both in vitro and in vivo models. Furthermore, upregulation of ULK1 expression through serum starvation conferred tolerance to osimertinib, reinforcing ULK1's role in d...