Ailanthone synergizes with PARP1 inhibitor in tumour growth inhibition through crosstalk of DNA repair pathways in gastric cancer.

ABSTRACT

In our previous research, we proved that ailanthone (AIL) inhibits the growth of gastric cancer (GC) cells and causes apoptosis by inhibiting P23. However, we still find some GC organoids are insensitive to AIL. We have done some sequencing analysis and found that the insensitive strains are highly expressed in PARP1. In this study, we investigated whether AIL can enhance the anti-tumour effect of PARPi in GC. CCK8 and spheroid colony formation assay were used to measure anti-tumour effects. SynergyFinder software was used to calculate the synergy score of the drug combination and flow cytometry was used to detect apoptosis. Western blot, IHC, IF tests were used to measure protein expression. Finally, nude mouse xenograft models were used to verify the in vitro mechanisms. High expression of PARP1 was found to be the cause of drug insensitivity. When AIL is paired with a PARP1 inhibitor, olaparib (OLP), drug sensitivity improves. We discovered that this combination functions by blocking off HSP90-BRCA1 interaction and inhibiting the activity of PARP1, thus in turn inhibiting the homologous recombination deficiency and base excision repair pathway to finally achieve synthetic lethality through increased sensitivity. Moreover, P23 can regulate BRCA1 in GC in vitro. This study proves that the inhibitory effect of AIL on BRCA1 allowed even cancer cells with normal BRCA1 function to be sensitive to PARP inhibitors when it is simultaneously administered with OLP. The results greatly expanded the scope of the application of PARPi.