Lung cancer is the leading cause of cancer deaths worldwide. More than 40% of lung cancers are classified as lung adenocarcinoma (LUAD), which is defined by pathological characteristics. Oncogenic mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKD) are found in a significant portion of LUAD. Such mutations, which present most commonly as small in-frame deletions in exon 19 (ex19del) or as point mutations in exon 21 (L858R), allow for EGFR activation, sensitivity to EGFR tyrosine kinase inhibitors (TKIs), and molecularly targeted therapy in this malignancy.
By analyzing the tumors of patients with LUAD, we identified two EGFR alterations that had not previously been reported in lung cancer: the EGFR kinase domain duplication (EGFR-KDD) and the EGFR-RAD51 fusion. While knowledge about common EGFR mutations (L858R or ex19del) has allowed for rational treatment of specific cohorts of LUAD, nothing was known about the EGFR-KDD and EGFR-RAD51 in LUAD. These mutationsâwhich we call EGFR rearrangementsâmaintain the wild type sequence of the EGFR TKD and could have mediated either sensitivity or primary resistance to EGFR-TKI therapy. The goal of these studies was to fill in this knowledge gap: to characterize a new type of EGFR alteration in LUAD, to determine the sensitivity of these rearrangements to therapy, and, along the way, to uncover more about the biology of EGFR.
Collectively, the research in this dissertation used in vitro and in silico models, as well as patient-derived data, to address a previously unrecognized potential mechanism of oncogenesis in lung cancer: EGFR rearrangements. These studies established EGFR-KDD and EGFR-RAD51 as bona fide recurrent oncogenes and therapeutic targets in LUAD. The work is already proving clinically relevant as these alterations have been identified in additional lung cancer patientsâwho may now have more targeted treatment options.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03182017-172104 |
| Date | 12 April 2017 |
| Creators | Gallant, Jean-Nicolas |
| Contributors | Sally York, Christine Lovly, Robert Coffey, Rebecca Cook, Christopher Williams |
| 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-03182017-172104/ |
| Rights | unrestricted, 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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