Determining Mechanisms of Response to Polo-Like Kinase 1 Inhibition In Non-Small Cell Lung Cancer

<p>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</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2016

Author dc:creator

• Goonatilake, Ruchitha

Contributors dc:contributor

• Faye Johnson
• Khandan Keyomarsi
• Lauren Byers

• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/700

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1744