Center for Molecular Medicine Cologne

Hillmer, Axel | Büttner, Reinhard - A 06

Identification of therapeutic vulnerabilities of KEAP1-mutated lung adenocarcinoma


Lung cancer is the leading cause of cancer-related death with lung adenocarcinoma (LUAD) as the most frequent subtype. KEAP1 is mutated in 15-20% of LUAD, a patient group with particularly poor prognosis. In situations of high reactive oxygen species (ROS), NRF2 initiates the expression of pro-survival genes that quench ROS. In KEAP1 mutated LUAD, the NRF2 pathway is constitutively active, allowing the cancer to cope with high ROS levels. This adaptation makes cancer cells resistant to radio- and chemotherapy. There is an urgent clinical need to develop new treatment strategies for patients with KEAP1 mutated LUAD. A promising strategy is to inhibit the NRF2 pathway. In the proposed project, we will evaluate the pathogenic role of individual KEAP1 mutations by screening our clinical cohort using immunohistochemistry and our recently developed expression assay that identifies tumors with NRF2 pathway activity. In addition, we will test for the functional consequences of specific KEAP1 mutations in vitro. Further, we will search for genomic alterations other than KEAP1/NFE2L2 mutations that can activate the NRF2 pathway. Finally, we will establish model LUAD cell lines with inducible KEAP1 activity to screen drugs with effects specific for KEAP1 mutated tumors. The effect of candidate drugs will be further characterized by proteomics and metabolomics. Overall, we will pave the way to new treatment strategies for a large group of LUAD patients with poor prognosis.

Figure 1


  • Classify large available cohorts with genomic data for transcriptomic activity of NRF2 pathway
  • Test for enrichment and depletion of specific gene mutations
  • Test functional relevance for NRF2 pathway activity in vitro
  • Screen drugs for interfering with the pathway activity in vitro
  • Janning, M. et al. Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM). Ann Oncol 33, 602-615 (2022).
  • Saleh, M.M. et al. Comprehensive Analysis of TP53 and KEAP1 Mutations and Their Impact on Survival in Localized- and Advanced-Stage NSCLC. J Thorac Oncol 17, 76-88 (2022).
  • Chen, J. et al. Genomic landscape of lung adenocarcinoma in East Asians. Nat Genet 52, 177-186 (2020).
  • Nahar, R. et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat Commun 9, 216 (2018).
Prof. Dr. Axel Hillmer CMMC Cologne
Prof. Dr. Axel Hillmer

Institute for General Pathology and Pathological Anatomy

CMMC - PI - A 06


+49 221 478 85643

Institute for General Pathology and Pathological Anatomy

Joseph-Stelzmann-Str. 26

50931 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Axel Hillmer

Link to PubMed

Prof. Dr. Reinhard Büttner CMMC Cologne
Prof. Dr. Reinhard Büttner

Institute for General Pathology and Pathological Anatomy

CMMC - PI - A 03

CMMC - Co-PI - A 06

Executive Board Member

+49 221 478 6320

+49 221 478 6360

Institute for General Pathology and Pathological Anatomy

Kerpener Str. 62

50937 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Reinhard Büttner

Link to PubMed

Group Members

Christina Ali Dousty Shahraki
Sascha Hoppe
Sonja Meemboor
Sebastian Michels
Ali Yazbeck

PhD students
Mohammad Ali (Shahrokh) Karimpour
Christoph Jonas
Marta Pistone

Master student
Minkyung (Rachel) Beak
Medical students
Marten Wenzel
Patrizia Pauls

Barbara Holz
Vanessa Richartz

Visiting scientist
Antonio Ungaro