ABSTRACT

Lung adenocarcinoma often carries driver mutations, such as EGFR mutations, which are effectively targeted by EGFR tyros ine kinase inhibitors (EGFR- TKIs) like osimertinib, a third- generation EGFR- TKI approved for treating T790M and other EGFR- activating mutations. However, the development of adaptive drug resistance remains a major challenge and is associated with poor prognosis in cancer therapy. Ganoderma microsporum immunomodulatory protein (GMI) has demonstrated anticancer properties in various cancers and exhibits synergistic cytotoxic effects when combined with several anticancer drugs. This study investigated the cytotoxic mechanisms of GMI on the lung cancer cell line H1975, which harbors the EGFR L858R/T790M double mutation, as well as on H1975/TR cells with osimertinib resistance. GMI treatment triggered apoptosis in H1975 cells, as indicated by plasma membrane phospholipid translocation and loss of mitochondrial membrane potential. GMI- treated cells displayed increased LC3BII and the development of acidic vesicular organelles, both of which are hallmarks of autophagy induction. Autophagy inhibition by 3- methyladenine and ATG gene silencing effectively decreased the cytotoxic effect of GMI, suggesting that GMI induces autophagic cell death in H1975/TR cells. This study is the first to reveal the novel role of GMI in inducing cytotoxic effects in H1975 cells and H1975/TR cells with osimertinib resistance through two different forms of cell death: apoptosis and autophagy, respectively.

Plain Language Summary

Lung cancer often involves mutations in the EGFR gene, especially in Asian patients. The drug osimertinib (Tagrisso) is com monly used to treat lung cancer with certain EGFR mutations, including the T790M resistance mutation. However, many patients either do not respond well at the beginning or eventually stop responding because their cancer becomes resistant. Ganoderma is a traditional medicinal mushroom. GMI, a fungal immunomodulatory protein derived from Ganoderma microsporum, has shown anticancer and antiviral effects. In this study, we tested GMI on H1975 lung cancer cells, which carry both the L858R and T790M EGFR mutations, as well as on a version of these cells that is resistant to osimertinib. We found that GMI can kill both regular H1975 cells and osimertinib-resistant H1975 cells, but through different mechanisms. In regular H1975 cells, GMI activates apoptotic pathways, but in resistant cells, it drives autophagic cell death. This study identified GMI’s ability to target osimertinib-resistant lung cancer cells, suggesting it may have potential as a new treatment strategy。

原文出處： https://doi.org/10.1111/bcpt.70143