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Title: Cellular Mechanisms Involved in Developing Resistance Against Multi Kinase Inhibitors in Colorectal Cancer
Researcher: Binayak Kumar
Guide(s): Sri Krishna Jayadev M
Keywords: Life Sciences,Biology and Biochemistry,Cell and Tissue Engineering
University: Shiv Nadar University
Completed Date: 2017
Abstract: Sorafenib and Regorafenib are small molecule multi-kinase inhibitors used as anticancer drugs for treatment of liver, kidney and colorectal cancers (CRC). These drugs are reported to inhibit both Tyrosine Kinases and Serin-Threonine Kinases. These are both surface associated and intracellular molecules such as Vascular Endothelial Growth Factor Receptors (VEGFR), Platelet Derived Growth Factor Receptors (PDGFR), Fibroblast Growth Factor (FGFR), RAF, BRAF etc. and are shown to be effective against both mutant and wild type BRAF. There are some preliminary clinical reports of patients showing resistance to these drugs on long term usage. Our study aimed at developing a resistant cell line model for the above drugs and to understand the pathways and mechanisms involved in drug resistance development. Resistant cell lines of HCT-116 and HT-29 were developed by culturing sensitive cell lines with increasing concentration of the drug. In this study, the involvement of JAK-STAT/ PI3K/AKT/mTOR and RAF-ERK signaling pathways was checked by expression profiling of molecules from these pathways by real time PCR and western blotting. Micro-RNA profiling by Next Generation Sequencing and proteome profiling by nano-UPLC-QTOF Mass-Spectroscopy were performed with sensitive and resistant cells to look for the differentially expressed proteins and mi-RNA s that regulate them to understand the overall alterations in cells during drug resistance development. In this study, it was found that JAK-STAT/ PI3K/AKT/mTOR pathways were suppressed in the sensitive cell lines when treated with the Sorafenib or Regorafenib but were found to be actively expressed in resistant models. JAK-STAT, PI3K/AKT, mTOR and RAF-ERK signaling pathways are known to be activated in cancer and helps in regular proliferation of cancer cells. But, as noticed from the above results, upon drug treatment, these pathways get suppressed thereby leading to cell death.
Appears in Departments:Department of Life Sciences

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chapter-1.pdf1.31 MBAdobe PDFView/Open
chapter-2.pdf2.08 MBAdobe PDFView/Open
chapter-3.pdf1.1 MBAdobe PDFView/Open
chapter-4.pdf1.96 MBAdobe PDFView/Open
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preliminary pages.pdf1.07 MBAdobe PDFView/Open
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