Dammert, Marcel Andre (2021). Characterization and therapeutic exploitation of molecular vulnerabilities in genetically defined lung cancer. PhD thesis, Universität zu Köln.
|
PDF
Dissertation_Marcel-Dammert-public.pdf - Published Version Download (17MB) | Preview |
Abstract
Lung cancer is one of the most common cancer types and responsible for the largest number of cancer-related deaths worldwide. Typically, lung cancer arises in individuals with heavy smoking background and only rarely in never-smokers. Various cells of origin within the lung give rise to distinct, molecularly heterogenous lung cancer subtypes with the two major subtypes non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Targeted therapy options also vary significantly between the specific subtypes and while oncogene-driven lung adenocarcinoma (LUAD) is already successfully treated with targeted drugs, no targeted therapies are available in SCLC. LUAD is often driven genetic alterations such as point mutations and rearrangements in genes of receptor tyrosine kinases (RTKs) like EGFR leading to aberrant activation of receptor tyrosine kinase signaling and oncogenic transformation. Mutation-selective small molecule RTK inhibitors have been developed to specifically kill oncogene-addicted cancer cells. Introduction of third generation EGFR inhibitor osimertinib substantially increased survival of EGFR-mutant LUAD patients but on-target resistance mutations such as EGFR G724S limit osimertinib efficacy leading to tumor relapse. Remarkably, we observed that second-generation EGFR inhibitor afatinib displayed selective activity against EGFR G724S in cell line and animal models. In contrast to osimertinib, afatinib still binds to EGFR G724S and reduces cellular viability, EGFR signaling, transformation and in vivo growth of EGFR G724S cells, therefore providing a possible treatment strategy for patients that relapse after osimertinib treatment due to EGFR G724S. Oncogenic gene fusions involving RET also lead to cellular transformation and LUAD tumorigenesis. Previously, multi-kinase inhibitors were used to treat RET-rearranged cancers with limited success due to lack of RET-specificity and RET gatekeeper mutations impeding inhibitor binding. We identified AD80, a type II kinase inhibitor that binds RET in the DFG-out conformation. AD80 displayed selective activity against common RET fusions KIFB-RET and CCDC6-RET and retained activity against RET V804M gatekeeper mutation. AD80 efficiently reduced RET- and downstream signaling as well as RET-associated gene expression. AD80 also displayed in vivo efficacy in CCDC6-RET patient-derived xenograft (PDX) models, demonstrating the potential of type II inhibitors as targeted therapy against RET-rearranged LUAD. In contrast to NSCLC, SCLC is defined by inactivation of tumor suppressors TP53 and RB1 and lacks targetable oncogenic drivers. Frequent activation of MYC transcription factor family members (MYC, MYCL, and MYCN) further accelerate tumor growth and aggressiveness. We found that activation of individual MYC family members entails differential molecular vulnerabilities. MYC overexpression is associated with high levels of DNA damage, repression of BCL2 expression and high apoptotic priming, leading to higher sensitivity towards Aurora kinase and MCL1 inhibition whereas high MYCL/MYCN expression is associated with resistance against these perturbations. Our study highlights that MYC status can be predictive for therapy response and might be used for molecularly-guided, patient stratification for future targeted therapy regimens in SCLC. A rare but very aggressive lung cancer type, NUT carcinoma is driven by BRD4-NUT fusion protein leading to large-scale epigenetic reprogramming and deregulated transcription of genes driving tumorigenesis. Using high-throughput viability screening, we identified that NUT carcinoma cells are preferentially sensitive against CDK9 inhibition. We observed, that CDK9 inhibition increases RNA Polymerase II pausing possibly reverting BRD4-NUT-mediated, transcriptional activation of pro-tumor genes warranting further investigation of CDK9 inhibition in NUT carcinoma.
Item Type: | Thesis (PhD thesis) | ||||||||
Translated abstract: |
|
||||||||
Creators: |
|
||||||||
URN: | urn:nbn:de:hbz:38-551165 | ||||||||
Date: | 1 December 2021 | ||||||||
Language: | English | ||||||||
Faculty: | Faculty of Mathematics and Natural Sciences | ||||||||
Divisions: | Faculty of Medicine > Pathologie und Neuropathologie > Institut für Pathologie | ||||||||
Subjects: | Life sciences Medical sciences Medicine |
||||||||
Uncontrolled Keywords: |
|
||||||||
Date of oral exam: | 1 December 2021 | ||||||||
Referee: |
|
||||||||
Refereed: | Yes | ||||||||
URI: | http://kups.ub.uni-koeln.de/id/eprint/55116 |
Downloads
Downloads per month over past year
Export
Actions (login required)
View Item |