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TC-03

Researching the role of Ganoderma microsporum immunomodulatory

protein (GMI) in KRAS inhibitor-resistant cancer cells

1
#,1
Wei-Ting Lin, Wei-Jyun Hua, Tung-Yi Lin* ,1,2,3

1 Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei,
Taiwan
2 School of Chinese Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
3 Traditional Chinese Medicine Glycomics Research Center, National Yang Ming Chiao Tung
University, Taipei, Taiwan
* E-mail: biotungyi@gmail.com

Abstract
KRAS mutations are the most common genetic alterations in lung cancer. Although targeting
KRAS proteins has historically been challenging, recent advances have led to developing drugs
that inhibit mutant KRAS proteins. However, long-term use KRAS G12C inhibitors often leads
to resistance, limiting its effectiveness. Ganoderma , a medicinal mushroom used in traditional
Chinese medicine for over 2,000 years, has demonstrated anti-cancer, antioxidant, antibacterial,
anti-inflammatory, and immune-modulating properties. One of its unique species, Ganoderma
microsporum immunomodulatory protein (GMI), exhibits potent immunomodulatory and anti-
cancer activities. Previous research showed that combining GMI with the KRAS G12C inhibitor
AMG510 significantly suppressed the growth of H358 non-small cell lung cancer (NSCLC)
cells harboring KRAS G12C mutations. However, whether GMI could target cells that are
resistant to KRAS G12C inhibitors remained unclear. This study aims to investigate whether GMI
can inhibit the growth of drug-resistant NSCLC cells and explore its underlying molecular
mechanisms. The results indicate that GMI effectively inhibits cells resistant to the KRAS G12C
inhibitors AMG510 and MRTX849 through the AXL pathway. Moreover, combining GMI with
KRAS G12C inhibitors yields enhanced inhibitory effects. Therefore, GMI has the potential to
address the problem of drug resistance caused by KRAS inhibitors.

Keywords: KRAS; AXL; Resistant; GMI