Lung cancer remains the leading cause of cancer related deaths in the United States despite a significant number of advancements in the molecular diagnosis and treatment of this disease. Recent genome wide expression analyses of human lung cancer has identified a number of receptor tyrosine kinases (RTKs) as overexpressed and potentially representing molecular drivers of lung cancer. Among these RTKs identified was EPHA2, which is highly expressed in lung cancer correlating to poor clinical outcomes. The role of EPHA2 in lung cancer, specifically in distinct molecular subtypes, is largely unknown. In this study, we dissected the role of EPHA2 in a variety of molecular subtypes of lung cancer and discovered that KRAS and EGFR(T790M) mutant lung cancers were most vulnerable to inhibition of EPHA2 by either genetic or pharmacological methods. We demonstrated functional evidence in vivo that the EPHA2 receptor is required for tumor growth and survival in both Kras(G12D) and EGFR(L858R+T790M) transgenic mouse models. We also showed that in lung cancer EPHA2 controls cell viability through a PI3K/mTOR dependent mechanism regulating apoptosis. Additionally, we identified a novel, ATP competitive EPHA2 RTK inhibitor, ALW-II-41-27, which was capable of inhibiting KRAS and EGFR mutant lung cancer cell viability both in vitro and in vivo. Overall these findings provide genetic, functional, mechanistic, and pharmacologic evidence that EPHA2 promotes the progression and survival of lung tumors. In addition, these findings provide rationale for the development of EPHA2 targeted therapeutics for clinical use.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03232015-094458 |
| Date | 24 March 2015 |
| Creators | Amato, Katherine Renee |
| Contributors | Deborah Lannigan, Jin Chen, Pierre Massion, Rebecca Cook |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03232015-094458/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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