Wang, Yue
(2023)
Integrative pharmacogenomic approaches to study and overcome drug resistance in cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Drug resistance is a major challenge in obtaining durable and long-lasting responses in either chemo-/targeted therapies or immunotherapies in cancer. For decades, great efforts have been made to address two essential questions: (1) what makes drug resistance, and (2) how to overcome drug resistance. In this thesis, we integrated multi-dimensional pharmacogenomic data from cancer cell lines and patients to systematically identify novel master regulators that contribute to chemo-/immunotherapy resistance (Chapter 2 and Chapter 3), as well as chemo-immunotherapy synergisms to overcome immunotherapy resistance (Chapter 4). Specifically, in Chapter 2, we established a knowledgebase of long non-coding RNAs (lncRNAs) associated with multi-drug resistance through integrating expression profile of 11,950 lncRNAs and response profile of 265 anti-cancer drugs in 1,005 cancer cell lines. We identified a novel lncRNA named ERINA, who is an estrogen responsive oncogenic lncRNA, can regulate multi-drug resistance and is associated with poor survival of estrogen receptor positive breast cancer patients. In Chapter 3, through an integrative analysis of lncRNA expression and tumor immune response in 9,626 tumor samples across 32 cancer types, we developed a lncRNA-based immune response (LIMER) score that can predict the immune cells infiltration and patient prognosis in multiple cancer types. By further integrating the lncRNA DNA methylation data, we identified tumor-specific lncRNAs that can potentially regulate tumor immune response in multiple cancer types. We validated that lncRNA EPIC1 can induce tumor immune evasion and immunotherapy resistance by suppressing tumor cell antigen presentation and interferon signaling. In Chapter 4, we integrated the expression profiles from patients received immunotherapy and half million post-treatment cancer cell line expression profiles, through which we characterized the first comprehensive landscape and mechanism for chemo-immunotherapy synergism. We validated a P21-activated kinase inhibitor (PAKi) and showed the compound can synergize with anti-PD-1 treatment via inducing mitophagy, which triggers the tumor secretion of CXCL10 through a mitochondrial double strand RNA and type I interferon dependent mechanism. Together, these three studies presented in this thesis will facilitate the ongoing pre-clinical efforts on establishing strategies to reverse chemotherapy and immunotherapy resistance.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
9 May 2023 |
| Date Type: |
Publication |
| Defense Date: |
18 January 2023 |
| Approval Date: |
9 May 2023 |
| Submission Date: |
27 March 2023 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
181 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Chemoimmunotherapy
Drug resistance
Pharmacogenomics
Computational Modeling
Cancer genomics |
| Date Deposited: |
09 May 2023 17:44 |
| Last Modified: |
09 May 2023 17:44 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44316 |
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