Universität zu Köln

Weiß, Jonathan (2011). Deciphering oncogene dependencies and signaling pathway alterations in non small cell lung cancer. PhD thesis, Universität zu Köln.

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Abstract

Lung cancer is the leading cause of cancer related death worldwide with 1.4 million cases in 2008. Thus, there is an unmet need to identify novel treatment options for lung cancer patients in the clinic and foster the understanding of tumor biology. The Ph.D. thesis presented here focuses on the identification and characterization of novel oncogenes that play a role in the onset of lung tumor development as well as on the characterization of signaling pathway recruitment downstream of oncogenic receptor tyrosine kinases (RTKs). In this regard, we were able to identify two genes encoding for protein kinases being causative for tumor development and furthermore we were able to functionally validate both genes as being the relevant target of the respective inhibitor in-vitro. In detail, we identified: - amplifications of the human version of v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene (cSRC) as being causative and predictive for the sensitivity towards the clinical approved Src-Abl inhibitor dasatinib - amplifications of the fibroblast growth factor receptor 1 (FGFR1) as being causative and predictive for the sensitivity towards the FGFR protein family inhibitor PD173074 - frequent amplifications of FGFR1 in squamous cell but no other type of NSCLC cells. Hence, we strongly suggest to treat patients suffering from FGFR1 amplified squamous cell lung tumors with FGFR1 inhibitors. Furthermore, we utilized in-vitro chemical-genomic approaches and genetic engineering to functionally validate both, cSRC and FGFR1, as the relevant targets of the respective inhibitors in amplified cell lines. And finally, we extended our already established high-throughput screening platform to be able to screen up to 1500 compounds as well as combinations of various signaling pathway inhibitors. To this end, we have screened 136 inhibitor combinations on 105 genetically defined cell lines to identify novel treatment options as well as specific signaling pathway recruitments within defined genetic conditions. Thus, amplifications of cSRC as well as FGFR1 lead to responsiveness towards small molecule inhibitors in NSCLC cells harboring amplification of either gene. We show that high throughput cell based screening of inhibitor combinations can be utilized to shed light into the complex recruitment of signaling pathways downstream of RTKs and lead to novel treatment strategies for patients suffering from lung cancer. And finally, we identified FGFR1 amplifications in up to 20% primary squamous cell lung cancer specimens, strongly suggesting to treat these patients with FGFR1 inhibitors.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Weiß, Jonathan jweiss@gmx.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-42338
Date:	2011
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Lungcancer, oncogene-dependency, screening, tyrosinekinase, FGFR1, cSRC, English
Date of oral exam:	4 April 2011
Referee:	Name Academic Title Hammerschmidt, Matthias Prof. Dr. Abken, Hinrich Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/4233