University of Kentucky UKnowledge Theses and Dissertations--Pharmacy College of Pharmacy 2017 GENE EXPRESSION PROFILES REVEAL ALTERNATIVE TARGETS OF THERAPEUTIC INTERVENTION FOR THE TREATMENT OF DRUG-RESISTANT NON-SMALL CELL LUNG CANCERS Madeline J. Krentz Gober University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0001-7761-6741 Digital Object Identifier: https://doi.org/10.13023/ETD.2017.309 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Krentz Gober, Madeline J., "GENE EXPRESSION PROFILES REVEAL ALTERNATIVE TARGETS OF THERAPEUTIC INTERVENTION FOR THE TREATMENT OF DRUG-RESISTANT NON-SMALL CELL LUNG CANCERS" (2017). Theses and Dissertations--Pharmacy. 78. https://uknowledge.uky.edu/pharmacy_etds/78 This Doctoral Dissertation is brought to you for free and open access by the College of Pharmacy at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Pharmacy by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Madeline J. Krentz Gober, Student Dr. Esther P. Black, Major Professor Dr. Dave Feola, Director of Graduate Studies GENE EXPRESSION PROFILES REVEAL ALTERNATIVE TARGETS OF THERAPEUTIC INTERVENTION FOR THE TREATMENT OF DRUG- RESISTANT NON-SMALL CELL LUNG CANCERS DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Pharmacy at the University of Kentucky By: Madeline J. Krentz Gober Lexington, Kentucky Director: Dr. Esther P. Black, Ph.D., Professor of Pharmaceutical Science Lexington, Kentucky 2017 Copyright © Madeline Krentz Gober, 2017 ABSTRACT OF DISSERTATION GENE EXPRESSION PROFILES REVEAL ALTERNATIVE TARGETS OF THERAPEUTIC INTERVENTION FOR THE TREATMENT OF DRUG- RESISTANT NON-SMALL CELL LUNG CANCERS More than 80% of lung cancer patients die from drug-resistant, metastatic disease. Our focus is to identify new drug targets and alternative therapeutic strategies to improve outcomes for this majority of lung cancer patients. We aimed to satisfy the need for new treatment approaches by leveraging the information gained from the development of two multigene biomarker predictors of Epidermal Growth Factor Receptor Inhibitors (EGFRI) response in Non-Small Cell Lung Cancer (NSCLC). From these data, we first identified TGFβ signaling as a possible modulator of EGFRI resistance and I hypothesized that TGFβ signaling participates in the development and maintenance of erlotinib-resistance and - sensitivity and regulates the gene expression of the miRNA comprising the signature of response. To identify novel putative treatment strategies for overcoming EGFRI resistance, we leveraged the raw data used to build the EGFRI-response predictors of NSCLC cells with divergent EGFRI responses using mathematical and protein-protein interaction modeling to identify a network of deregulated proteins in EGFRI-resistant cells. From this analysis, we identified a drug combination that is kills EGFRI-resistant NSCLC cells and further study will confirm if this novel strategy translates into a clinically utilizable option for the treatment of EGFRI-resistant NSCLC. KEYWORDS: Pharmacogenomics; EGFR; TGFβ; Non-Small Cell Lung Cancer; Casein Kinase 2; CK2 and MEK combination treatment. Madeline Krentz Gober Student’s Signature July 10th 2017 Date GENE EXPRESSION PROFILES REVEAL ALTERNATIVE TARGETS OF THERAPEUTIC INTERVENTION FOR THE TREATMENT OF DRUG- RESISTANT NON-SMALL CELL LUNG CANCERS By: Madeline Krentz Gober Dr. Esther P. Black Director of Dissertation Dr. Dave Feola Director of Graduate Studies July 10th 2017 Date ACKNOWLEDGEMENTS This dissertation could not have been completed without the dedication and support of many friends, colleagues, mentors, and family. First, I thank my advisor, Dr. Penni Black for encouraging and allowing me to grow as a well-rounded individual rather than just a bench top scientist. Thank you for forcing me to face the things I was afraid of and allowing me to embrace my creativity, develop my own directions and make this body of work my own. To my committee, thank you each for sharing your unique backgrounds, expertise and styles with me. To Dr.Dave Feola, thank you for being warm and supportive, but also judicious. To Dr. Sylvie Garneau-Tsodikova, thank you for being inviting, and sensible but ambitious. Thank you for also sharing my love of civil service and helping me develop new community-based programs here at UK. To Dr. Rina Plattner, thank you for being honest and kind but critical. To our collaborators, Dr. Katherine Thompson and Dr. Robert Flight, thank you for helping me see, model and analyze our data in new ways. Without your input, a substantial fraction of this work would not have been possible. I would like to thank my family for being so supportive. I thank my parents, Kim and Doug Krentz, who encouraged me to be determined and creative and taught me that I could achieve anything I was willing to work hard enough for. I thank my husband, Redding Gober, for encouraging me to pursue anything that makes me happy and always daring me to dream bigger. I asked a lot when I asked you to move this far with me, but I think we’re both happy that you did and we’re better for it. I firmly believe that together we can accomplish anything we want to and I’m happy you share my life ambitions. Thank you also for tolerating that horses are the key to my sanity and for embracing my passion. Finally, to my friends, lab mates, and department colleagues, thank you for all that you’ve done to make this possible. It truly takes a village to raise a successful PhD student, and I can’t thank you all enough for helping me troubleshoot my problems, sharing your reagents and instruments, participating in my adventures teaching third grade science, and for simply listening when I needed to gripe. I solved more problems than I can count by simply walking down the hall and asking someone and I can’t thank you all enough for being there when I needed you most. iii TABLE OF CONTENTS ACKNOWLEDGMENTS............................................................................ iii LIST OF TABLES.................................................................................... viii LIST OF FIGURES................................................................................... ix CHAPTER 1 .......................................................................................................... 1 A LUNG CANCER OVERVIEW .................................................................... 1 Overview of Cancer .................................................................. 1 Lung Cancer Epidemiology ..................................................... 3 Common Driver Mutations in Lung Tumors .......................... 4 Targeted Therapies in NSCLC .............................................. 12 B EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) ........................ 17 EGFR Activation and Signaling ............................................. 17 EGFR Mutations in Non-Small Cell Lung Cancers (NSCLC) ................................................................................... 20 Inhibition of EGFR in Lung Cancer Therapy ....................... 22 C TRANSFORMING GROWTH FACTOR BETA (TGFβ) BIOLOGY AND SIGNALING ............................................................................................. 26 TGFβ Signaling ....................................................................... 26 The Role of TGFβ in Lung Cancer ....................................... 30 Targeting TGFβ Signaling in Cancer: A Paradox Problem ................................................................................................... 34 iv D CASEIN KINASE 2 (CK2) BIOLOGY ...................................................... 35 The Kinase ............................................................................... 35 CK2 in Cancer ........................................................................