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Genetic alterations and sensitivity to anti-cancer drugs in colorectal cancer cells
대장암 세포의 유전자 변이와 항암제 반응성

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Authors
권연주
Advisor
김태유
Major
융합과학기술대학원 분자의학 및 바이오제약학과
Issue Date
2015-02
Publisher
서울대학교 대학원
Keywords
colorectal cancerKRASanti-cancer drugs
Description
학위논문 (석사)-- 서울대학교 융합과학기술대학원 : 분자의학 및 바이오제약학과, 2015. 2. 김태유.
Abstract
Colorectal cancer (CRC), the third most common cancer in the world, develops through complicated genetic mutations that occur in a stepwise progression. Therefore, examining cells for genetic alterations has been considered important in furthering research into the treatment of CRC.
In support of such research, we first investigated the effects of mutation of KRAS oncogene, which is the most common genetic alteration in CRC. To determine the effects of KRAS substitutions in different CRC cell lines, we initially generated plasmids for 7 KRAS mutation subtypes that occur frequently. We then compared downstream signaling and KRAS activity in transfected HEK293 cells and CRC cell lines harboring KRAS mutations. In HEK293 cells, the G12D and Q61L mutant substitutions increased RAS downstream signaling, and KRAS activity was markedly increased in both G12S and G13D. In contrast, among 18 CRC cells, SW480 harboring KRAS G12V exhibited the greatest level of signaling activation and KRAS activity was noticeably high in HCT15 CRC cells harboring G13D. Therefore, it seems that mutation at codon 12 and 13 activates K-RAS signaling and activity in CRC.
To investigate further the relationship between genetic alterations and drug sensitivity, we initially confirmed the presence of genetic alterations of major 5 genes (NRAS, KRAS, BRAF, PI3KCA and PTEN) in 18 CRC cell lines by using Sanger sequencing. Then, we selected hot-spot mutation of 5 genes based on Cancer Cell Line Encyclopedia data (CCLE). Drug sensitivities of the 18 cell lines to 6 anti-cancer drugs (5-FU, oxaliplatin, SN-38, AZD6244, regorafenib and PLX4720) were evaluated. Due to non-computable IC50 values, the drug sensitivities of the 18 cell lines were arranged by survival at clinically relevant concentrations. Mann Whitney U test results indicated a significant association between PIK3CA mutation and oxaliplatin sensitivity.
In addition, we confirmed that cell lines with a BRAF mutation showed sensitivity to AZD6244 and PLX4720.
In conclusion, the presence of different effects of KRAS substitutions on CRC and the presence of different relationships between genetic alterations and drug sensitivity are indicative of variability in CRC cell lines.
Language
English
URI
https://hdl.handle.net/10371/133362
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Theses (Master's Degree_분자의학 및 바이오제약학과)
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