Abstract
Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.
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Acknowledgements
This work was supported by the National Key Research and Development Program of China (2021YFC2400600, 2021YFE0103100), NFSC (81925035), Department of Science and Technology of Guangdong Province (High-level new R&D institute 2019B090904008, High-level Innovative Research Institute 2021B0909050003), the Scientific and Technological Innovation Leading Talent Project in Zhongshan City (LJ2021001), the Scientific Research and Innovation Team Project in Zhongshan City (CXTD2022011), and Research Foundation of Binzhou Medical University (BY2019KJ03). We also thank the Molecular Imaging Center, TEM lab at the Institutional Center for Shared Technologies and Facilities of SIMM, CAS, and the National Center for Protein Science Shanghai, CAS.
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TTL and YZH designed the research and performed data analysis. TTL, WX, and GHC carried out the experiments. LL, YH, and JLZ participated part of the experiments. TTL wrote the manuscript. WWL and XFG analyzed the manuscript formal. YZH revised the manuscript. All of the authors have read and approved the final manuscript. The authors declare no competing financial interest.
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Lin, Tt., Xiong, W., Chen, Gh. et al. Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages. Acta Pharmacol Sin 45, 867–878 (2024). https://doi.org/10.1038/s41401-023-01205-4
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DOI: https://doi.org/10.1038/s41401-023-01205-4