Inhibition of KRAS G12D mutant with Small Molecules
- 주제(키워드) 도움말 KRAS , Apoptosis , KRAS G12D mutations , NSCLC , Colorectal cancer , Therapy , MAPK , PI3K
- 발행기관 강릉원주대학교 일반대학원
- 지도교수 도움말 이대희
- 발행년도 2023
- 학위수여년월 2023. 2
- 학위명 석사
- 학과 및 전공 도움말 일반대학원 웰니스바이오산업학과
- 세부분야 해당없음
- 실제URI http://www.dcollection.net/handler/kangnung/000000011360
- UCI I804:42001-000000011360
- 본문언어 영어
초록/요약 도움말
Patients with cancer involving KRAS mutations are resistant to therapeutics that target epidermal growth factor receptor and show poor outcomes. In addition, effective treatments that target G12D in KRAS have not been developed. Thus, therapeutic agents targeting the G12D mutation in KRAS are needed. In this study, we identified the Q2a compound, a quinazoline-based derivative that specifically acts on the KRAS G12D mutation. This compound induced cell apoptosis by reducing phosphorylation of AKT in the PI3K pathway downstream of KRAS. Q2a compound specifically inhibited the growth of KRAS G12D mutant cells. In addition, cells with the KRAS G12D mutation were more sensitive to Q2a compound compared to the sensitivity of wild-type cells and those with other KRAS mutations, resulting in apoptosis. Treatment with the Q2a compound also decreased C-RAF phosphorylation in the MAPK pathway, which is downstream of KRAS. In KRAS G12D-mutated colorectal cancer xenografts, Q2a compound inhibited tumor production without significant liver toxicity. Q2a compounds show potential as therapeutic agents that target KRAS G12D mutations in colorectal and pancreatic cancers.
more목차 도움말
Ⅰ. Introduction
Ⅱ. Materials and Methods
2.1. Materials
2.2. Cell lines and cell culture
2.3. Protein analysis by Western blot
2.4. Cell proliferation assay
2.5. Clonogenic survival assay
2.6. Apoptosis assay
2.7. Measurement of intracellular KRAS activity
2.8. Colorectal cancer xenografts and treatments
2.9. Measurement of Q2a compound KRAS binding by thermal shift assay
2.10. Statistical analysis
Ⅲ. Results
3.1. Screening of small molecules targeting KRAS G12D
3.2. Concentration and time-dependent cell growth inhibitory effect in KRAS G12D
mutant cells and wild-type cells of colorectal cancer and lung cancer cells when
Q2a compound was treated
3.3. Concentration and time-dependent apoptosis effect in KRAS G12D mutant cells and wild-type cells of colorectal cancer and lung cancer cells when Q2a compound was treated
3.4. Apoptosis by Q2a compound, KRAS downstream related protein expression change
3.4.1. Effect of reducing apoptosis-related protein expression in KRAS G12D mutant cells by treatment with Q2a compound
3.4.2. Effect of reducing the expression of KRAS downstream-related proteins in KRAS G12D mutant cells by treatment with Q2a compound
3.5. Difference in gene expression between Q2a-treated group and control group in LIM 1215 KRAS G12D cells
3.6. Q2a compound suppresses mutant KRAS G12D colorectal cancer in xenograft models
Ⅳ. Conclusion
Ⅴ. References
