Fig. 5
Co-operativity between XL102 and Venetoclax. A IC50 values of Venetoclax in Venetoclax sensitive (VenS) and Venetoclax resistant cells (VenR). B Venn diagram showing common genes associated with treatment and are compared with the significantly deregulated genes found between the sensitive untreated and resistant untreated. C GSEA plot showing the enrichment of genes related to p53 mediated signaling in VenR cells after XL102 treatment for 24 h. The Normalized Enrichment Score (NES) was found to be -2.0638618 and FDR q-value was 0.0087 D Principle component analysis of VenR cells after 24 h of XL102 treatment and the pathways enriched in treatment E Heatmap representation of deregulated genes associated exclusively with treatment in VenR F To investigate pharmacological interactions between XL102 and Venetoclax, incremental doses of Venetoclax were applied while the dose of XL102 was kept constant at 0.05 μM or 0.1 μM. The cell growth inhibition data indicated that combination of the drugs is highly synergistic as demonstrated by Chou-Talalay method of combination index (CI) analysis G AML blasts were treated with 0.1uM of XL102 along with 5 different concentrations of Venetoclax followed by determination of Combination index. H Basal level expression of apoptotic proteins and p53 in MOLM13 Venetoclax sensitive versus resistant cells. I Change in expression of antiapoptotic protein after combinatorial treatment with XL102 and venetolcax in VenR cells J Representative image of tumors from animals treated with combination of Venetoclax and XL102. K Venetoclax and XL102 combination treatment resulted in reduction of mean tumor weight (in grams) and mean tumor volume of AML xenografts as compared to control, Venetoclax alone or XL102 alone