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Unraveling Synthetic Lethality in Triple-Negative Breast Cancer: Identifying Novel Gene Targets to Overcome Chemotherapy Resistance

Shao, Shuai
http://rave.ohiolink.edu/etdc/view?acc_num=osu1682008618372068

Abstract Details

2023, Doctor of Philosophy, Ohio State University, Pharmacy.
Triple-negative breast cancer (TNBC) accounts for 15-20% of breast cancer cases, yet it disproportionately contributes to 35% of breast cancer deaths. In addition, chemotherapy resistance is a significant challenge in TNBC treatment. In this study, we aimed to identify potential synthetic lethal targets for cisplatin/doxorubicin treatment in TNBC and investigate the potential of a cell-death double knock-out library to discover synergistic lethal gene pairs for TNBC therapy. Initially, we identified the MDA-MB-231 cell line as the most representative model for TNBC chemotherapy-poor responders by comparing genomic profiles from TNBC cell lines and patient samples. We then conducted a genome-wide CRISPR-Cas9 screen and RNAseq analysis in MDA-MB-231 cells. Our analysis confirmed the involvement of known essential genes in DNA damage repair and regulation of DNA replication pathways, such as BCL2L1, ATM, CDC25B, and NBN, in sensitizing cells to cisplatin/doxorubicin. Moreover, we identified hundreds of previously unrecognized genes and pathways related to DNA repair, G2/M DNA damage checkpoint, AMPK signaling, and mTOR signaling. The observed differences between transcriptomic responses and essential pathways from the CRISPR screen suggest a complex regulatory system in the cellular response to DNA-damaging drugs. By integrating various data analysis methods and biological experimental approaches, we pinpointed several promising genes, such as MCM9 and NEPPS, which could serve as potential drug targets to overcome chemoresistance. We also utilized our lab's custom CRISPR double knock-out library, which leverages the XDeathDB database for candidate gene selection. This comprehensive platform provides insights into 12 cell death modes and 149 cell death hallmark genes. We aim to create a cell-death double knock-out library using these genes and perform double knock-out screening on MDA-MB-231 cells. The identified synergistic lethal gene pairs may serve as potential drug targets for TNBC treatment. Our approach efficiently identified essential genes with potential synthetic lethal interactions with cisplatin/doxorubicin. Furthermore, it provided insights into developing a cell-death double knock-out library for uncovering synergistic lethal gene pairs. This study presents new possibilities for combination therapies in chemo resistant TNBC patients and establishes the foundation for developing targeted, personalized treatments that exploit synthetic lethality.
Lang Li (Advisor)
138 p.
Bioinformatics; Pharmacology; Pharmacy Sciences
TNBC Crispr Screening Synthetic Lethality Chemoresistance

Recommended Citations

Citations

  • Shao, S. (2023). Unraveling Synthetic Lethality in Triple-Negative Breast Cancer: Identifying Novel Gene Targets to Overcome Chemotherapy Resistance [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1682008618372068

    APA Style (7th edition)

  • Shao, Shuai. Unraveling Synthetic Lethality in Triple-Negative Breast Cancer: Identifying Novel Gene Targets to Overcome Chemotherapy Resistance. 2023. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1682008618372068.

    MLA Style (8th edition)

  • Shao, Shuai. "Unraveling Synthetic Lethality in Triple-Negative Breast Cancer: Identifying Novel Gene Targets to Overcome Chemotherapy Resistance." Doctoral dissertation, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu1682008618372068

    Chicago Manual of Style (17th edition)

osu1682008618372068
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© 2023, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.