Investigating the genomic basis for cancer cell response to multi-AGC kinase inhibitor AT13148

The PI3K-AKT cellular growth and survival signalling pathway is commonly deregulated in a wide range of cancers. The novel candidate anticancer drug AT13148 is a multi-AGC kinase whose targets include PI3K-AKT signalling effectors, and it is currently in phase I clinical trial. Recently, growth inhibition and gene mutation data for this compound have been produced from the Genomics of Drug Sensitivity in Cancer (GDSC) cell line panel at the Wellcome Trust Sanger Institute. When bioinformatics pharmacogenomic analyses were performed for common cancer genes, PTEN mutations were statistically significantly associated with AT13148 sensitivity, whereas KRAS mutations were significantly associated with resistance. Amplifications of KIT and PDGFRA, both individually and together with KDR were associated with potent AT13148 sensitivity. Whole exome pharmacogenomic analyses also revealed a further fifteen genes mutationally associated with sensitivity to AT13148, including VHL mutations predominantly in kidney cancer cell lines and rare mutations in CETN3, NOP10 and CLDND2 occurring in highly sensitive cell lines. IC50 comparison analyses between AT13148 and other drugs included on the GDSC database, SRC inhibitors Dasatinib, AZD-0530 and A-770041 gave strong IC50 correlations with AT13148 in kidney cancer cell lines. Future genomic analyses of AT13148 GDSC data should investigate the mutational characteristics of AT13148-sensitive PTEN mutated cell lines and further examine the genomic features of AT13148-responsive kidney cancer cell lines. Transcriptomics analysis approaches should also be developed and integrated into these investigations. Laboratory experiments should also be developed to test the pharmacogenomic associations with AT13148 response predicted in this study using a distinct set of cell lines. Results of such experiments, if consistent with predictions, may potentially assist with patient stratification for phase II clinical trial of AT13148.