Abstract 415: Metformin sensitizes non-small cell lung cancer to CDK4/6 inhibitor treatment by reducing lysosomal trapping

Abstract Hyperactivation of cyclin D1-CDK4/6 signaling is correlated with tumour metastasis, and poor prognosis in patients with non-small cell lung cancer (NSCLC), suggesting the therapeutical potential of targeting CDK4/6 to treat NSCLC. Our preliminary data suggest CDK4/6 inhibitors are sequestered in lysosomes in NSCLC cells, a phenomenon termed lysosomal trapping that is correlated with intrinsic resistance. It’s promising to search for new compounds that could be co-administered with CDK4/6 inhibitors to reduce lysosomal trapping, hence enhancing the sensitivity of NSCLC cells. Here, we find metformin reduces the activity of lysosomal pathway through genome-wise analyses; in accordance, metformin efficiently reduces lysosomal trapping of CDK4/6 inhibitors in NSCLC cells. Biologically, metformin enhances the suppressing effects of CDK4/6 inhibitors on cell cycle progression, cell proliferation, and colony formation. Mechanistically, metformin suppresses lysosomal trapping by: 1) reducing translocation of TFEB into nuclei that leads to decreased lysosome biogenesis, and 2) disrupting lysosomal acidic environment through reduced V-ATPase activity and decreased interaction between LAMP1/LAMP2 and TMEM175. Clinically, combined treatment with metformin and CDK4/6 inhibitors significantly retards the growth of mouse xenografts and tumour cell organoids. Taken together, our study provides a new mechanistic dimension on utilizing metformin to treat NSCLC by reducing lysosomal trapping, therefore, increasing cellular sensitivity to CDK4/6 inhibitors. Citation Format: Yaqi Liu, Yalei Wang, Ni Zhang, Haijuan Xiong, Lipan Zhao, Jiping Xie, Xiaofeng Duan, Dongsheng Yue, Shuo Qie. Metformin sensitizes non-small cell lung cancer to CDK4/6 inhibitor treatment by reducing lysosomal trapping [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 415.