Cellular Mechanisms Involved In Developing Resistance Against Multi-Kinase Inhibitors In Colorectal Cancer. | Shiv Nadar University
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Cellular Mechanisms Involved In Developing Resistance Against Multi-Kinase Inhibitors In Colorectal Cancer.

Sorafenib and Regorafenib are multi-kinase inhibitors used as oral anti-cancer drugs for the treatment of advanced stages of various cancers including colorectal cancer (CRC). It inhibits various surface-associated growth factor receptors and its downstream intracellular kinases. There are some preliminary clinical reports showing resistance to Regorafenib on long-term use. The mechanism of acquiring resistance during treatment with this drug is not well studied.
Our study aims at developing sorafenib and regorafenib resistant cell model systems. This was achieved by culturing the Sensitive (HT-29 and HCT-116) cells in the presence of these drugs. To study the drug sensitivity for these cell lines we performed MTT-assay and Propidium Iodide staining techniques. Different signaling cascades like JAK-STAT, PI3K-AKT-mTOR and RAF-ERK and pathways regulating Apoptosis were analyzed by real time-PCR and western blot. Proteome and miRNA profiling was done by Mass spectrometry (MS) and   miRNA Seq. respectively.  This data was analyzed and compared using various bioinformatics tools. 

We found that cells cultured regularly in the presence of the drug showed survival even in high doses of the drug when compared to the sensitive cells. Further the alteration in expression of different molecules from different signaling cascades showed their involvement in acquiring resistance to these drugs. Further proteome and mi-RNA profiling data revealed some regulatory networks between protein expression and their regulation at post-transcriptional level. Various signaling components were found upregulated whereas mi-RNA’s that target these molecules were suppressed in the resistant cells. Many of the known tumor suppressor proteins like BRCA1 and PARP15 were found downregulated whereas the mi-RNA’s that target them were upregulated. The exact involvement of all these pathways needs to be further studied in detail. 
 

Department: 
Life Sciences
Year: 
2017
Student Name: 
Binayak Kumar
Faculty Advisor: 
Co-Faculty Advisor: 

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