Date Available

8-4-2021

Year of Publication

2021

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

First Advisor

Dr. Esther P. Black

Abstract

Immune checkpoint inhibitors (ICIs), especially those that target programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), have been shown to provide substantial clinical benefit in many patients with non-small cell lung cancer (NSCLC). While these therapeutic agents can be highly effective in the correct context, the biological systems that malignant cells draft from normal activities of the cell are poorly characterized. Tumor cell-specific expression of PD-L1 is likely important for clinical benefit from PD-1 and PD-L1 inhibitors. It is known that PD-L1 is inappropriately expressed in many cancers harboring mutations in the RAS family of genes. The KRAS gene is mutated in as many as 30% of NSCLC tumor and drives tumor proliferation. Because there are no FDA-approved KRAS-targeting agents available for NSCLC patients, ICI therapy has been used in patients with tumors harboring mutations in the KRAS gene with clinical success. However, utilization of these therapies will remain hindered until there is a more complete understanding of the mechanisms governing the expression of targets of ICIs, specifically of PD-L1. The work in this dissertation explores the role of the tyrosine phosphatase, SHP-2. SHP-2 has been scrutinized as an important signaling molecule in a variety of cancers that links the activity of several signaling cascades as a regulator of KRAS, resulting in the clinical development of inhibitors of SHP-2. The work encompassed in these studies takes two complementary approaches to explore the role of SHP-2 in control of PD-L1 expression. First, publicly available real-world genomic information was used to establish a connection between the activity and/or expression of SHP-2 and PD-L1 in tumors and how expression relates to response to ICI therapy. Second, this work further sought to elucidate the molecular mechanism by which SHP-2 impacts the expression of PD-L1 in an NSCLC cell line model system. From these investigations, this work established that SHP-2 and PD-L1 have an expression relationship in clinical samples that may impact response to ICI therapies and experimentally identified a possible mechanism by which SHP-2 impacts PD-L1 expression in NSCLC.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.362

Funding Information

This work was supported by the University of Kentucky department of Pharmaceutical Sciences (March 2017-August 2021).

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