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