Hillmer, Axel | Büttner, Reinhard - A 06

Identification of therapeutic vulnerabilities of KEAP1-mutated lung adenocarcinoma

Prof. Dr. Axel Hillmer
Prof. Dr. Axel Hillmer

Institute for General Pathology and Pathological Anatomy

CMMC - PI - A 06

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Institute for General Pathology and Pathological Anatomy

Joseph-Stelzmann-Str. 26

50931 Cologne

Prof. Dr. Reinhard Büttner
Prof. Dr. Reinhard Büttner

Institute for General Pathology and Pathological Anatomy

CMMC - PI - A 03

CMMC - Co-PI - A 06

Executive Board Member

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Institute for General Pathology and Pathological Anatomy

Kerpener Str. 62

50937 Cologne

Introduction

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.

Schematic of NRF2 function. Under physiological conditions, KEAP1 mediated the degradation of NRF2. In 20% of NSCLC, the NRF2 pathway is constitutively active, leading to drug tolerance. We aim to clarify which mutations lead to this constitutive pathway activity and which drugs can inhibit the resistance causing activity.

Approach

  • 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

Lab Website

For more research information, please check Prof. Hillmers website. 

Affiliations - Axel Hillmer

Affiliations - Reinhard Büttner

Publication Record on PubMed - Axel Hillmer

Publication Record on PubMed - Reinhard Büttner

2024 (up to June)
  • Alidousty C, Becker A, Binot E, Hillmer AM, Merkelbach-Bruse S, Budde B, Bassmann I, Rappl G, Wolf J, Eich ML, Noh KW, Buettner R, and Schultheis AM (2024). Frequency and functional characterization of fusion genes in squamous cell carcinoma of the lung. Gene895, 148018. doi:10.1016/j.gene.2023.148018.
     
  • Garcia-Marquez MA, Thelen M, Bauer E, Maas L, Wennhold K, Lehmann J, Keller D, Nikolic M, George J, Zander T, Schroder W, Muller P, Yazbeck AM, Bruns C, Thomas R, Gathof B, Quaas A, Peifer M, Hillmer AM, von Bergwelt-Baildon M, and Schlosser HA (2024). Germline homozygosity and allelic imbalance of HLA-I are common in esophagogastric adenocarcinoma and impair the repertoire of immunogenic peptides. J Immunother Cancer12. doi:10.1136/jitc-2023-007268.
     
  • Plum PS, Hess T, Bertrand D, Morgenstern I, Velazquez Camacho O, Jonas C, Alidousty C, Wagner B, Roessler S, Albrecht T, Becker J, Richartz V, Holz B, Hoppe S, Poh HM, Chia BKH, Chan CX, Pathiraja T, Teo AS, Marquardt JU, Khng A, Heise M, Fei Y, Thieme R, Klein S, Hong JH, Dima SO, Popescu I, Hoppe-Lotichius M, Buettner R, Lautem A, Otto G, Quaas A, Nagarajan N, Rozen S, Teh BT, Goeppert B, Drebber U, Lang H, Tan P, Gockel I, Schumacher J, and Hillmer AM (2024). Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker. Clin Transl Med14, e1723. doi:10.1002/ctm2.1723.
2023
  • Alidousty C, Becker A, Binot E, Hillmer AM, Merkelbach-Bruse S, Budde B, Bassmann I, Rappl G, Wolf J, Eich ML, Noh KW, Buettner R, and Schultheis AM (2024). Frequency and functional characterization of fusion genes in squamous cell carcinoma of the lung. Gene 895, 148018. doi:10.1016/j.gene.2023.148018.
  • Arolt C, Dugan M, Wild R, Richartz V, Holz B, Scheel AH, Bragelmann J, Wagener-Ryczek S, Merkelbach-Bruse S, Wolf J, Buettner R, Catanzariti L, Scheffler M, and Hillmer AM (2023). KEAP1/NFE2L2 Pathway Signature Outperforms KEAP1/NFE2L2 Mutation Status and Reveals Alternative Pathway-Activating Mutations in NSCLC. J Thorac Oncol 18, 1550-1567. doi:10.1016/j.jtho.2023.07.016.
     
  • Arolt C, Hoffmann F, Nachtsheim L, Mayer M, Guntinas-Lichius O, Buettner R, von Eggeling F, Klussmann JP, Hillmer A, Quaas A, Klein S, and Wolber P (2023). The extracellular matrix landscape in salivary gland carcinomas is defined by cellular differentiation via expression of three distinct protein modules. J Pathol 260, 148-164. doi:10.1002/path.6071.
     
  • Muller P, Velazquez Camacho O, Yazbeck AM, Wolwer C, Zhai W, Schumacher J, Heider D, Buettner R, Quaas A, and Hillmer AM (2023). Why loss of Y? A pan-cancer genome analysis of tumors with loss of Y chromosome. Comput Struct Biotechnol J 21, 1573-1583. doi:10.1016/j.csbj.2023.02.024.

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