Page 92 - 2025中醫藥與天然藥物聯合學術研討會-中醫藥與天然藥物的挑戰Ｘ機遇與未來大會手冊

GMI, an Immunomodulatory Protein from Ganoderma microsporum,

Suppresses Lung Tumor Progression via EGFR Degradation and KRAS

Pathway Modulation

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Wei-Jyun Hua, Hsin Yeh, Zhi-Hu Lin, Ai-Jung Tseng, Li-Chen Huang, Tung-Yi
Lin* ,1,2,3

1 Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei
11221, Taiwan
2 School of Chinese Medicine, National Yang Ming Chiao Tung University, Taipei 11221,
Taiwan
3 Traditional Chinese Medicine Glycomics Research Center, National Yang Ming Chiao Tung
University, Taipei 11221, Taiwan

* E-mail: tylin99@nycu.edu.tw

Abstract

GMI, a fungal immunomodulatory protein isolated from Ganoderma microsporum, exhibits
potent antitumor activity in lung cancer; however, its efficacy in tumors harboring oncogenic
EGFR or KRAS mutations has not been fully delineated. In lung cancer cells expressing EGFR,
GMI interacts with the extracellular domain of EGFR, triggering phosphorylation at Tyr1045

and subsequent clathrin-mediated endocytosis. This process facilitates EGFR degradation and
suppresses downstream oncogenic signaling cascades. Functional assays revealed that GMI
significantly inhibits the proliferation of cells carrying either wild-type or mutant EGFR,
whereas genetic silencing of EGFR nullifies GMI's antineoplastic effects in vitro and in vivo.

Concurrently, GMI exerts notable therapeutic effects in KRAS-mutant lung cancer cells.
Transcriptomic profiling and bioinformatic analyses indicate that GMI modulates signaling
pathways associated with KRAS, particularly MAPK and PI3K-AKT axes. In A549 cells
harboring KRAS G12S , GMI reduces KRAS-GTP levels and diminishes phosphorylation of

ERK1/2 and AKT. In contrast, treatment of H358 cells (KRAS G12C ) with GMI leads to
attenuated AKT activity while paradoxically enhancing ERK phosphorylation. In vivo studies
further substantiate these findings, as GMI administration significantly suppresses tumor
progression in both LLC1 syngeneic and H358 xenograft mouse models. Importantly, co-

administration of GMI with the KRAS G12C -selective inhibitor AMG510 results in sustained
inhibition of KRAS activity and yields superior tumor growth suppression compared to
monotherapies. Together, this study identify GMI as a dual-action therapeutic agent capable of
targeting both EGFR and KRAS oncogenic pathways, providing a novel strategy for the

treatment of genetically defined subsets of lung cancer.

Keywords: Ganoderma microsporum; GMI; EGFR; KRAS; Lung cancer

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