Hillmer, Axel | Büttner, Reinhard - A 03

Lung cancer is the leading cause of cancer-related death. KEAP1 is mutated in 15% of non-small cell lung cancer (NSCLC), a patient group with particularly poor prognosis. In situations of high reactive oxygen species (ROS), NRF2 initiates the expression of genes that quench ROS. In KEAP1 mutated NSCLC, the NRF2 pathway is constitutively active, allowing the cancer to cope with high ROS levels resulting in resistance to various therapies. There is an urgent clinical need to develop new treatment strategies for patients with KEAP1 mutated NSCLC. In the previous funding period, we have classified KEAP1 mutations in NRF2 pathway activating and not-activating. 

By genome editing, we have generated syngeneic cell line pairs with and without functional KEAP1, have characterized their response to high ROS levels, their NRF2 pathway activity, proliferation rate, and performed a drug screen. In the proposed project for the new funding period, we will validate the efficacy of these drugs as treatment of KEAP1-mutated NSCLC and evaluate their toxicities. Further, we will characterize the connection of the effective drugs with the NRF2 pathway in NSCLC by analyzing NRF2 pathway activity, expression of related genes, proteomic and glutathione redox system metabolite measurements. Finally, we will investigate the efficacy of the combination of the identified drugs with chemotherapy in vitro and in vivo using a mouse xenograft model. Overall, we will pave the way to new treatment strategies for a large group of NSCLC patients with poor prognosis.

• Drug screen of syngeneic NSCLC cell line pairs with and without active NRF2 pathway
• Generation of inducible NRF2 knock down cell lines
• Proteomics of syngeneic cell line pairs after ROS induction and treatment
• In vitro and in vivo test of combination therapies targeting the NRF2 pathway

For more research information, please check Professor Hillmers lab website. 

• Center for Molecular Medicine Cologne (CMMC)
• CRC 1310: Predicting molecular mechanisms of adaptation to chemoradiation therapy in cancer
• CRC 1310: The influence of stroma-metastasis interaction on tumor evolution
• Genomic pathology: Cancer genomics to understand tumor characteristics and vulnerabilities

• Center for Molecular Medicine Cologne (CMMC)
• Institute for Pathology, University Hospital of Cologne
• CRC 1310: Vorhersage von Therapieeffekten und des Rezidiven aggressiver B-Zell-Lymphome (C03*)
• CRC 1530: Proteogenomische Charakterisierung des Mantelzell-Lymphoms (C03) C3&Z02
• National Network Genomic Medicine Lungenkrebs (nNGM)
• Center for Integrated Oncology (CIO) Cologne