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Interactions of EGFR/IGF-1R Signaling in NSCLC - A Systems Biology Approach

Müller, Benedikt Felix

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Abstract

Lung cancer is the leading cause of cancer‐related deaths worldwide with 50,000 new cases per year in Germany and 220,000 in the USA. Non‐small cell lung cancer (NSCLC) is the most prevalent variant, with the majority of cases classifying as the adenocarcinoma subtype. Advances in molecular diagnostics have revealed driving mutations in some tyrosine kinase receptors (TKRs), such as the EGF receptor (EGFR). Other TKRs like the IGF‐I receptor (IGF‐1R) have been implied in NSCLC carcinogenesis. Consequently, treatment strategies have evolved to include inhibitors against these TRKs (tyrosine kinase inhibitors, TKIs), but only with temporal benefit for the patient. Evidence pointing towards an important role of IGF‐1 signaling in the evasion of inhibition of EGFR lead to double inhibition of EGFR and IGF‐1R being tested in the clinics. Phase I and II trials were promising, but a phase III study failed to demonstrate benefit for the primary end point of progression‐free survival after 12 weeks. My project used a systems biology approach to investigate the role of the dynamic crosstalk between the signaling from EGFR and IGF‐1R on NSCLC cells to better define the effects of pathway interaction and find causes for the failure of clinical combination treatment. To generate meaningful quantitative data for the phenotypical modeling of cell behavior, I established partly novel evaluation algorithms for 2D migration (in cooperation with the group of Dr. F. Matthäus) and 3D invasion (in cooperation with the group of Dr. D. Drasdo). In cooperation with the group of Prof. T. Höfer I could successfully establish a first unified ODE model of EGFR and IGF‐1R signaling in NSCLC cells from quantitative time resolved pathway activation data. Even though microarray analysis of EGF stimulated NSCLC cells revealed upregulation of migration associated genes, phenotypical assays showed that NSCLC cell migration was dependent on a more complex signaling environment than double stimulation with EGF and IGF‐1. On the other hand, I was able to show rescue of the NSCLC migratory behavior by IGF‐1 stimulation after EGFR inhibition in a full medium setting, further corroborating the important role of the interaction between these two growth factors for the early spread of NSCLC. The migration data I generated is currently used in the development of an agentbased model of NSCLC migration by the group of Dr. F. Matthäus. The data presented here and the associated computational evaluation algorithms and models will serve as the basis for the integrated multiscale modeling of the complex conditions governing NSCLC migration and the relevant cell signaling. Thus my work constitutes an important contribution towards understanding the intricate signaling responsible for the early spread of NSCLC and resistance against inhibition of particular TRKs.

Item Type: Dissertation
Supervisor: Klingmüller, Prof. Dr. Ursula
Place of Publication: Heidelberg
Date of thesis defense: 28 July 2015
Date Deposited: 05 Aug 2015 07:10
Date: 2015
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Service facilities > German Cancer Research Center (DKFZ)
Medizinische Fakultät Heidelberg > Pathologisches Institut
Subjects: 570 Life sciences
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