Abstract B1-02: Correlation between oncogenic mutations, signaling pathways, and efficacy of platinum-based drugs against colorectal cancers

The purpose of this study is to correlate genetic mutations, amino-acid variants, signaling pathways with platiunum based drug activity to shed light on personalized treatment of cancer. Platinum anticancer drugs such as cisplatin, carboplatin, and oxalipaltin are widely used to treat a variety of cancers. Although DNA is the molecular target for these platinum therapies, their efficacies, toxicities, and resistance mechanisms vary widely among various categories and sub-categories of cancers. To comprehend this great variability, an integrated analysis was performed to determine the impact of somatic mutations on protein functions, signaling pathways, and drug activity (sensitivity or resistance) among the US National Cancer Institute (NCI) 60 human tumor cell lines based on Z-scores to predict a priori treatment outcome using CellMiner (http://discover.nci.nih.gov/cellminer). Specifically, somatic mutations of significantly mutated genes from the cancer genome atlas (TCGA) were analyzed along with the driver genes (oncogenes and tumor suppressor genes) from catalogue of somatic mutations in cancer (COSMIC) for total 188 genes that belong to more than 20 different signaling pathways. The functional impact of individual amino-acid variant for each gene and its correlation with the activity of carboplatin, cisplatin and oxaliplatin for each cancer cell line were explored. Particular attention was given to colon cancer for which nearly 40% of tumors are known to have mutated KRAS (Kirsten rat sarcoma viral oncogene homolog) gene. Resulting analysis revealed that colon cancer cell lines with KRAS mutations for codon 12 (G12V-mutant from SW620 cell line) and codon 13 (G13D-mutant from HCT116 and HCT15 cell lines) correlated with the sensitivity to oxaliplatin. Conversely, oxaliplatin resistant HCC2998 colon cancer cell line did not show any correlation with mutated KRAS for codon 146 (A146T-mutant). Notably, all the colon cancer cell lines were resistant to both carboplatin and cisplatin with no correlation to the KRAS mutants. Based on our integrated analysis we further predicted gene networks related to oxaliplatin activity for colon cancer. The network includes the epidermal growth factor (EGFR) signaling pathway that involves PIK3CA, PIK3CG and MTOR from the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) (PIK3/mTOR) pathway, and JAK3 from Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in addition to KRAS from Mitogen-activated protein kinases (MAPK) pathway. We conclude that instead of considering all mutations of a gene in the same way to assess their clinical significance, it may be beneficial to categorize them into different classes based on their functional impact and efficacies towards the anti-cancer drugs for personalized treatment. Similar analytical approach is being extended to non-small cell lung and ovarian cancers where platinum therapies are widely used. S. Tripathi gratefully acknowledges the support through a training fellowship from a grant by the Cancer Prevention Research Institute of Texas (Grant No. RP140113 to R.N.Bose). Citation Format: Swarnendu Tripathi, Louiza Belkacemi, Margaret S. Cheung, Rathindra N. Bose. Correlation between oncogenic mutations, signaling pathways, and efficacy of platinum-based drugs against colorectal cancers. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-02.