Date of Graduation

8-2016

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Faye Johnson

Committee Member

Khandan Keyomarsi

Committee Member

Lauren Byers

Committee Member

Walter Hittelman

Committee Member

Jing Wang

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. The discovery of genetic alterations in some patients (~15%) has made it possible to use targeted therapies without the use of chemotherapy. To identify potential therapeutic targets in NSCLC, we systematically evaluated two cancer cell line databases with sensitivity data for a broad range of drugs. We identified polo-like kinase 1 (Plk1) as the most promising target for further investigation based on a subset of sensitive cell lines and inhibitors that were in advanced clinical development. To identify potential biomarkers of response and mechanisms of Plk1 inhibitor-induced apoptosis, we performed an integrated analysis of gene and protein expression, gene mutation, and drug sensitivity using three Plk1 inhibitors (volasertib, BI2536, GSK461364) in a large panel of NSCLC cell lines. We observed that the NSCLC cell lines have varying sensitivities to Plk1 inhibition, with a smaller subset demonstrating sensitivity to all three inhibitors. Plk1 inhibition led to increase of cells with 4N DNA content, but only sensitive cell lines underwent substantial apoptosis following Plk1 inhibition. NSCLC lines with a high epithelial-mesenchymal transition gene signature score (i.e., mesenchymal lines) were more sensitive to Plk1 inhibitors than epithelial lines (p

Available for download on Wednesday, August 16, 2017

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