Ganoderma microsporum immunomodulatory protein combined with KRAS^G12C inhibitor impedes intracellular AKT/ERK network to suppress lung cancer cells with KRAS mutation

KRAS mutations are tightly associated with lung cancer progression. Despite the unprecedented clinical success of KRAS^G12C inhibitors, recurrent mechanisms of resistance and other KRAS mutations require further therapeutic approaches. GMI, a protein from the medicinal mushroom Ganoderma microsporum, possesses antitumor activity; whereas, the biological function of GMI on regulating KRAS mutant lung cancer cells remains unknown. Herein, RNA-sequencing and bioinformatics showed that GMI may regulate KRAS-modulated MAPK and PI3K-AKT pathways in A549 (KRAS^G12S) cells. Further experiments demonstrated that GMI inhibited KRAS activation and suppressed ERK1/2 and AKT signaling in A549 cells. Intriguingly, GMI inhibited AKT signaling but increased phosphorylation of ERK in H358 (KRAS^G12C) cells. GMI significantly suppressed tumor growth in LLC1 cells-allograft and H358 cells-xenograft mice. GMI showed a synergistic effect with KRAS^G12C inhibitors in inhibiting cell growth, KRAS activation and KRAS-mediated downstream signaling, leading to apoptosis in H358 cells. Combination of GMI and KRAS^G12C inhibitor, AMG 510, resulted in more durable inhibition of tumor growth and KRAS activity in H358 cells-xenograft mice. This study highlights the potential of GMI, a dietary fungal protein, as a viable therapeutic avenue for KRAS-mutant lung cancer in combination with KRAS^G12C inhibitors.