Leveraging the human kinome for anticancer agent cytotoxicity potency prediction

Kınalı, Meriç.
Cancer is the second deadly disease globally. Cell signaling cascades with altered protein kinase activities induce the majority of the hallmarks in cancer such as proliferation, angiogenesis, invasion, and metastasis. The major subtype of primary liver cancer, Hepatocellular carcinoma (HCC) has limited therapeutic options. In this study, we presented a regression model, which was applied initially on cytotoxic bioactivity data obtained from HCC cells treated with 120 kinase inhibitors called CanSyL dataset. The model then extended on publicly available datasets. The model uses human kinome tree topology-based classes of protein kinases. Small-molecule kinase inhibitors can act on other pathways by “off-target” or “pathway cross-talk” effects in addition to their previously reported targets. Our objective in this study was to predict these off-target effects as potential new targets by regularizing the regression space based on the kinome tree topology. Our regression model was tested on the CanSyL dataset by applying leave-one-out cross-validation and achieved promising predictions (median RMSE between 2.5-4 %) for the kinase inhibitor vulnerability matrix based on the regularization of the human kinome tree, with no bias in the estimates. Then we scaled up our approach to the public datasets (CCLE and GDSC). Some of the kinase inhibitors were identified as outliers based on their individual RMSE. They were significantly different from the kinase inhibitor groups that they belong to, according to the Mann-Whitney U test (p<0.05). This difference in specificity suggests that outlier inhibitors are more specific inhibitors while non-outlier inhibitors are mostly general multi-kinase inhibitors.


The Mechanism of anti tumorigenic effects of 15-lox-1 in colon cancer
Çimen, İsmail; Banerjee, Sreeparna; Department of Biology (2012)
Colorectal cancer is the 4th most widespread cause of cancer mortality. One of the pathways that are involved in the development of colorectal cancer is the arachidonic acid metabolizing lipoxygenase (LOX) pathway. Inflammatory molecules formed from this pathway exert profound effects that may exacerbate the development and progression of colon and other cancers. 15 lipoxygenase-1 (15-LOX-1) is a member of LOX protein family that metabolizes primarily linoleic acid to 13-(S)-HODE. Several lines of evidence ...
Identification of gene mutations involved in drug resistance in liver cancer using RNA-SEQ data analysis
Shojaei, Mona; Atalay, Rengül; Acar, Aybar Can; Department of Bioinformatics (2016)
A significant concern in cancer research is the detection of cancer associated somatic mutations. Liver cancer is the 5th most common and 2nd deadliest cancer in the world. Several somatic mutations were previously reported in liver cancer but their relations to chemotherapeutic response was not studied in detail. In this study, the relationship between mutation status and drug treatment response of well-differentiated Huh7 and poorly-differentiated Mahlavu liver cancer cells were analyzed. The RNA-Seq data...
Synthesis of novel indole-isoxazole hybrids and evaluation of their cytotoxic activities on hepatocellular carcinoma cell lines
Hawash, Mohammed; Kahraman, Deniz Cansen; Ergun, Sezen Guntekin; Cetin-Atalay, Rengul; BAYTAŞ, SULTAN (2021-12-01)
Background Liver cancer is predicted to be the sixth most diagnosed cancer globally and fourth leading cause of cancer deaths. In this study, a series of indole-3-isoxazole-5-carboxamide derivatives were designed, synthesized, and evaluated for their anticancer activities. The chemical structures of these of final compounds and intermediates were characterized by using IR, HRMS, H-1-NMR and C-13-NMR spectroscopy and element analysis. Results The cytotoxic activity was performed against Huh7, MCF7 and HCT116...
Investigaton of chemopreventive properties of Urtica Dioica L., in MCF-7 and MDA231 breast cancer cell lines
Güler, Elif; İşcan, Mesude; Department of Biology (2011)
Cancer is a major health problem in developing world with mostly unsufficient treatment. Cancer prevention through dietary modification appears to be a practical and cost effective possibility. The aim of present study is to investigate the chemical components of “Urtica diocia,L (U. diocia) grown in Turkey” and the possible protective potential of its aqueous extract against breast cancer cell lines. U. diocia was extracted by maceration method which was performed for 6,12, 24, and 36 hours, at 50°C, 37°C,...
Structural mapping and network analysis of patient-specific mutations in glioblastoma
Kaya, Tuğba; Tunçbağ, Nurcan; Doğan, Tunca; Department of Bioinformatics (2018)
Cancer is one of the most common cause of death worldwide. It occurs as a result of a collection of somatic deviations from normal state. Therefore, many efforts have been invested to profile mutations in different types of tumors; such as, the Cancer Genome Atlas (TCGA) which deposits multiple omic data for more than 11,000 tumor samples. In this thesis, we present a pipeline which retrieves patient-specific mutation data in Glioblastoma from TCGA, maps these mutations on the protein structures in Protein ...
Citation Formats
M. Kınalı, “Leveraging the human kinome for anticancer agent cytotoxicity potency prediction,” Thesis (M.S.) -- Graduate School of Informatics. Bioinformatics., Middle East Technical University, 2019.