PLEK gene expression was re ported to play a potential role in blocking neoplastic transformation. Taken together, our protein structure based approach appears effective in the identification of new putative cancer genes for future cancer biology studies. Case study identification of new putative biomarker for anticancer drug sensitivity Identifying anticancer drug response markers through computational methods is highly promising for cancer precision therapy. In this study, we sought to evalu ate the putative drug sensitivity genes by incorporating drug pharmacological data, protein pocket information, and cancer cell line mutation profiles from the CCLE. We mapped 64,000 missense mutations and frameshift inducing indels in 1,659 genes onto the protein pocket regions across approximately 1,000 different cancer cell lines.

A total of 104 missense mutations and 36 frame shift indels were mapped in the pocket regions of 34 proteins. Next, we compiled 458 genes that displayed drug sensitivity or resistance to 130 anticancer drugs. Our statistical analysis indicated that the genes har boring pocket mutations were enriched within antican cer drug response genes. Here, we provided an example of identifying putative biomarker for anticancer drug responses. The BAX gene had the highest number of cancer cell line mutations in the pocket regions. We first examined the BAX gene on vinorelbine, an anti mitotic chemotherapy drug that is approved for breast cancer and non small cell lung cancer treatment by the U. S. Food and Drug Administration.

We divided the cancer cell lines into two subgroups BAX gene mutated and BAX gene wild type, using all of BAX genes somatic mutation profiles. We found that the IC50 of BAX mut versus BAX WT cancer cell lines on vinorelbine was not significantly different. Then, we divided the cancer cell lines into two subgroups BAX pocket mutated and BAX wild type using the BAX protein pocket somatic mutation profiles. Interestingly, the IC50 value of the BAX Pmut cancer cell lines harboring pro tein pocket mutations on vinorelbine was significantly lower than that of BAX WT cancer cell lines. Similar patterns were observed when we examined the other two drugs midostauin and tipifamib. This example, plus the general patterns we identified, suggested that our integrative ap proach using protein pockets, somatic mutation, and drug pharmacological information is promising to iden tify anticancer drug response biomarkers in the emer ging era of cancer precision therapy.

Discussion Recently, several large scale cancer genome sequencing projects, such as the TCGA and ICGC, have released gen omic landscapes of human cancer genomes, especially somatic mutations. Entinostat Such landscapes consist of a small number of mountains and a much larger number of hills.