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Synergistic Co-Targeting of KRAS and MYC in KRAS-Dependent Cancer Using Ligand-Directed Inverted Chimeric RNAi Molecules
Synergistic Co-Targeting of KRAS and MYC in KRAS-Dependent Cancer Using Ligand-Directed Inverted Chimeric RNAi Molecules
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104805
- ISBN
- 9798291554869
- DDC
- 616.99
- 서명/저자
- Synergistic Co-Targeting of KRAS and MYC in KRAS-Dependent Cancer Using Ligand-Directed Inverted Chimeric RNAi Molecules
- 발행사항
- [Sl] : The University of North Carolina at Chapel Hill, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 181 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-02, Section: B.
- 주기사항
- Advisor: Pecot, Chad V.
- 학위논문주기
- Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2025.
- 초록/해제
- 요약Activating mutations in the GTPase KRAS are responsible for driving nearly 25% of all cancer types. Despite extensive research, effective KRAS inhibitors remained elusive until recently. The discovery of covalent molecules that irreversibly bind to the KRASG12C mutant protein, present in approximately 15% of cancer patients, facilitated the development of KRASG12C-specific inhibitors. However, clinical evidence of rapidly acquired resistance to KRASG12C inhibitors underscores the need for therapies that can overcome these challenges and target non-KRASG12C mutations. Mutant KRAS cooperates with the transcription factor MYC to promote tumorigenesis, and dual targeting of KRAS and MYC has shown synergistic anti-cancer effects in murine models. We have developed highly potent siRNAs against KRAS and MYC that inhibit downstream signaling and key cancer phenotypes. Using an endo-nucleolytic DNA bridge, we created an RNAi molecule that link MYC- and KRAS-targeting siRNAs in "serial" and "inverted" chimeric conformations. Compared to both serial chimeras and individual siRNAs, the inverted chimeric siRNA designs achieved superior gene silencing, resulting in ~40-fold reduction in cell viability and loss of tumorigenic potential. Mechanistic studies reveal that endosomal cleavage of the chimeric siRNA generates 2'-deoxythymidine (dT) 5'-terminal overhangs on the antisense strand, further enhancing target silencing in a dose-dependent manner. This chimeric siRNA design establishes proof-of-concept for dual KRAS and MYC silencing and represents a new molecular strategy for co-targeting any two genes of interest with broad implications.
- 일반주제명
- Oncology
- 일반주제명
- Genetics
- 일반주제명
- Medicine
- 일반주제명
- Molecular biology
- 일반주제명
- Biochemistry
- 키워드
- Mutations
- 키워드
- Cancer
- 키워드
- Ligands
- 키워드
- Oncogenes
- 기타저자
- The University of North Carolina at Chapel Hill Genetics and Molecular Biology
- 기본자료저록
- Dissertations Abstracts International. 87-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520260202104805
■006m o d
■007cr#unu||||||||
■020 ▼a9798291554869
■035 ▼a(MiAaPQ)AAI32165576
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616.99
■1001 ▼aChareddy, Yogitha Sai.
■24510▼aSynergistic Co-Targeting of KRAS and MYC in KRAS-Dependent Cancer Using Ligand-Directed Inverted Chimeric RNAi Molecules
■260 ▼a[Sl]▼bThe University of North Carolina at Chapel Hill▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a181 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-02, Section: B.
■500 ▼aAdvisor: Pecot, Chad V.
■5021 ▼aThesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2025.
■520 ▼aActivating mutations in the GTPase KRAS are responsible for driving nearly 25% of all cancer types. Despite extensive research, effective KRAS inhibitors remained elusive until recently. The discovery of covalent molecules that irreversibly bind to the KRASG12C mutant protein, present in approximately 15% of cancer patients, facilitated the development of KRASG12C-specific inhibitors. However, clinical evidence of rapidly acquired resistance to KRASG12C inhibitors underscores the need for therapies that can overcome these challenges and target non-KRASG12C mutations. Mutant KRAS cooperates with the transcription factor MYC to promote tumorigenesis, and dual targeting of KRAS and MYC has shown synergistic anti-cancer effects in murine models. We have developed highly potent siRNAs against KRAS and MYC that inhibit downstream signaling and key cancer phenotypes. Using an endo-nucleolytic DNA bridge, we created an RNAi molecule that link MYC- and KRAS-targeting siRNAs in "serial" and "inverted" chimeric conformations. Compared to both serial chimeras and individual siRNAs, the inverted chimeric siRNA designs achieved superior gene silencing, resulting in ~40-fold reduction in cell viability and loss of tumorigenic potential. Mechanistic studies reveal that endosomal cleavage of the chimeric siRNA generates 2'-deoxythymidine (dT) 5'-terminal overhangs on the antisense strand, further enhancing target silencing in a dose-dependent manner. This chimeric siRNA design establishes proof-of-concept for dual KRAS and MYC silencing and represents a new molecular strategy for co-targeting any two genes of interest with broad implications.
■590 ▼aSchool code: 0153.
■650 4▼aOncology
■650 4▼aGenetics
■650 4▼aMedicine
■650 4▼aMolecular biology
■650 4▼aBiochemistry
■653 ▼aMutations
■653 ▼aCancer
■653 ▼aLigands
■653 ▼aOncogenes
■653 ▼aKirsten rat sarcoma
■690 ▼a0992
■690 ▼a0369
■690 ▼a0564
■690 ▼a0487
■690 ▼a0307
■71020▼aThe University of North Carolina at Chapel Hill▼bGenetics and Molecular Biology.
■7730 ▼tDissertations Abstracts International▼g87-02B.
■790 ▼a0153
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358886▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
