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Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages

Acta Pharmacologica Sinica volume 45, pages 867–878 (2024)Cite this article

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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Fig. 1: Characterization of the liposomes and cellular uptake study.
Fig. 2: Macrophage repolarization and EMT reversal.
Fig. 3: In vitro anti-tumor effect and glycolysis regulation by Lf-Lipo.
Fig. 4: In vitro anti-angiogenesis study.
Fig. 5: In vivo imaging and distribution of Lf-Lipo.
Fig. 6: Anti-tumor efficiency of Lf-Lipo in Osi-resistant human NSCLC in vivo.
Fig. 7: Remodeling tumor microenvironment.

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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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Authors and Affiliations

  1. Department of Pharmacy, Binzhou Medical University Hospital, Binzhou, 256603, China

    Ting-ting Lin, Xin-fu Gao & Wen-wen Lv

  2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Ting-ting Lin, Gui-hua Chen, Yang He, Li Long & Yong-zhuo Huang

  3. Artemisinin Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510450, China

    Wei Xiong, Gui-hua Chen & Yong-zhuo Huang

  4. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528437, China

    Wei Xiong, Jia-lin Zhou & Yong-zhuo Huang

  5. NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients, Shanghai, 201203, China

    Yong-zhuo Huang

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Contributions

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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Correspondence to Wen-wen Lv or Yong-zhuo Huang.

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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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