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A Systems Chemical Biology Approach for Dissecting Differential University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School June 2018 A Systems Chemical Biology Approach for Dissecting Differential Molecular Mechanisms of Action of Clinical Kinase Inhibitors in Lung Cancer Natalia Junqueira Sumi University of South Florida, [email protected] Follow this and additional works at: https://scholarcommons.usf.edu/etd Part of the Molecular Biology Commons Scholar Commons Citation Junqueira Sumi, Natalia, "A Systems Chemical Biology Approach for Dissecting Differential Molecular Mechanisms of Action of Clinical Kinase Inhibitors in Lung Cancer" (2018). Graduate Theses and Dissertations. https://scholarcommons.usf.edu/etd/7685 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. A Systems Chemical Biology Approach for Dissecting Differential Molecular Mechanisms of Action of Clinical Kinase Inhibitors in Lung Cancer by Natalia Junqueira Sumi A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy with a concentration in Cancer Biology Department of Cell Biology, Microbiology and Molecular Biology College of Arts and Sciences University of South Florida Major Professor: Uwe Rix, Ph.D. Nicholas J. Lawrence, Ph.D. Keiran S. Smalley, Ph.D. W. Douglas Cress, Ph.D. Eric B. Haura, MD. Forest White, PhD. Date of Approval: March 31, 2018 Keywords: Proteomics, lung cancer, RNA-seq, network, bioinformatics, drug combination Copyright © 2018, Natalia Junqueira Sumi DEDICATION This dissertation is primarily dedicated to me. It is the result of much perseverance and hard work, and a commitment to achieving better quality of life and financial security for my family. Secondly, I dedicate this work to my family: knowing that at the end of this project we would be together and happy inspired me to push forward, especially when times were tough. I am lucky that my husband is working in the same field and understands that all this work is necessary for our future. He has always believed that I could succeed as a researcher and he reminded me of my strength when I had forgotten. Finally, I dedicate this work to my lovely son, God’s great gift in my life. He inspired me to finish this thesis and to always give the best of myself in my work. I hope one day he will be proud of me and understand how important higher education can be in a person’s life. ACKNOWLEDGMENT First, I would like to thank Dr. Uwe Rix for the opportunity to do my PhD work in his lab, exploring a question I have been interested in since my undergraduate studies: What are the complete target profiles of drugs and what are their mechanisms of action in cells? I am grateful for his guidance throughout these last four years and I am leaving the program with confidence in my abilities to work independently as a scientist. Most importantly, I am grateful for his support during the most significant time of my life, welcoming and caring for my amazing baby boy. I also want to extend a huge thank you to the members of the Rix lab for all their support, input during lab meetings and company during afternoon coffee breaks: To Brent Kuenzi for his help with the chemistry and data analyses for the CDK project. To Lily Rix for all her help and support, for organizing both the laboratory and girls’ nights, and especially for her smile, even after I had asked so many questions. To Claire Knezevic for her wonderful example of professionalism and organization, and being an overall amazing person. To Gabriela Wright for not only being an incredible laboratory technician and manager, but for inspiring in me the perseverance to always grow professionally. To Annamarie Bryant for her kindness and enthusiasm, especially at times when my own fervor waned. To Claudia Ctortecka for contributing not only to this project, but to the well-being of myself and my son. She is an angel sent to me from the other side of the world and I would not have made it through this project, or my pregnancy, without her. To Grace Ward for her friendship and companionship during coffee breaks and lunches. I would like to thank my thesis committee for their time and guidance during this project. It was a complex mechanism of action to solve and their input was fundamental in determining the answer. I would like to thank Dr. White in particular for taking the time to travel to Florida and participate as an external chair. I am grateful to my funding sources, especially Circle of Hope for Cancer Research Inc. for enabling me to expand my research, and the University of South Florida for granting me a travel award to Italy for a bioinformatics course and presentation of my research. I would also like to extend my gratitude to the Cancer Biology PhD Program for providing such high quality lectures and support to its students. A special thanks to Cathy, Kim, and Janet for making the entire graduate student experience, from registration to graduation, less stressful. I would like to thank Moffitt Cancer Center and the Research Cores in proteomics, molecular genetics, flow cytometry, and microscopy. Thank you for your time and patience in training me and answering all my questions. Finally, I would like to thank my mother for putting her life on pause to come and help me. Mama, thank you for driving the long distances, grocery shopping, cooking, cleaning, keeping us company in the NICU, loving us unconditionally, and being a lovely grandma to my baby boy. Thank you for taking such great care of our baby boy and encouraging me to finish my degree. Thank you for being on my side one more time. I could not have done this without you and I will try my best to be as wonderful a mother to my son as you have been to me. Thank you also to my brother, whose kind heart has been such a blessing at this very special time in my life. TABLE OF CONTENTS List of Tables ............................................................................................................................. iii List of Figures ............................................................................................................................ iv Abstract vii Chapter One: Introduction ........................................................................................................... 1 Lung cancer .................................................................................................................... 1 Statistics for 2017 ................................................................................................ 1 Types of Lung Cancer .......................................................................................... 2 Treatment ........................................................................................................................ 4 Treatment for NSCLC .......................................................................................... 4 Treatment for SCLC ............................................................................................. 8 Immunotherapy .................................................................................................. 10 Medical need ................................................................................................................. 12 Drug off-targets ............................................................................................................. 13 Integrated analysis for identification of off-targets .......................................................... 18 Mass-spectrometry-based proteomics approaches ............................................ 18 Peptide identification and quantification ............................................................. 24 Protein identification and quantification .............................................................. 25 RNA-sequencing ........................................................................................................... 27 Systems biology ............................................................................................................ 28 Chapter Two: Chemoproteomics reveals novel protein and lipid protein targets of clinical CDK4/6 inhibitors in lung cancer .................................................................. 33 CDK4/6 inhibitors in lung cancer.................................................................................... 33 Experimental design ...................................................................................................... 38 Materials and methods .................................................................................................. 39 Cell culture and reagents ................................................................................... 39 Viability assays .................................................................................................. 40 Immunoblotting .................................................................................................. 40 Kinase assays .................................................................................................... 40 Chemical synthesis ............................................................................................ 41 c-Palbociclib ........................................................................................... 41 c-Ribociclib ............................................................................................
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