Garmultinone A synergizes with oncolytic virus to induce tumor cell apoptosis through YAP1 degradation

Background Oncolytic virotherapy has shown clinical promise, however only a small fraction of cancer patients can benefit. Purpose To overcome this limitation, we screened for a natural small-molecule compound that can potentiate the oncolytic efficacy of oncolytic viruses, thereby achieving more effective antitumor activity with low toxicity. Methods We screened a natural small-molecule compound library to identify the most potent sensitizer of VSVΔ51. Next, we performed RNA-seq analysis to elucidate the mechanisms underlying the antitumor effects of the combined treatment, followed by experimental validation. Finally, we established in vivo glioma and breast cancer models to verify the antitumor efficacy and associated mechanisms of the combination therapy. Results Through a natural small-molecule compounds screening, we identified Garmultinone A (GA) as the top sensitizer for VSVΔ51 oncolytic virotherapy. Further investigation reveals that GA cooperated with VSVΔ51 to downregulate YAP1 expression, thereby promoting tumor cell apoptosis. Mechanistically, GA/VSVΔ51 combination treatment promotes YAP1 degradation via proteasomal pathway. Finally, our results show that the GA/VSVΔ51 combination therapy markedly enhanced treatment outcomes in preclinical models of malignant glioma and breast cancer. Conclusion Our study identifies the synergistic combination of GA and VSVΔ51 as a promising therapeutic paradigm against cancers.