Center for Molecular Medicine Cologne

Hillmer, Axel - assoc. RG 09

Identification of therapeutic vulnerabilities of KEAP1-mutated lung adenocarcinoma

Abstract

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 (gene name: NFE2L2) 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. We evaluate the pathogenic role of individual KEAP1 mutations by screening our clinical cohort using immunohistochemistry and an 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

We will apply this concept to treatment naïve EAC biopsies and normal tissues and will systematically identify cell-type specific alterations that correspond to treatment response and relapse. We will validate our findings using a large collection of EAC tissues for targeted assays and by experiments in tissue culture. Overall, we will be able to identify functional changes in CAFs and other tumor components that will help to explain the clinical course of an EAC patient and that provide new opportunities for intervention.

Clinical and Medical Relevance

KEAP1 mutated LUAD has a poor prognosis. We will establish a better definition of NRF2 activated tumors than relying on the non-silent mutations in KEAP1 or NFE2L2 and will identify drugs that target the NRF2 pathway. Such drugs bear a great potential to improve treatment response in the large group of advanced stage non-small cell lung cancer patients with NRF2 pathway activating mutations, a patient subgroup with particularly high medical need for better therapies (in Germany: 2,500 per year).

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  • Tan JHJ, Kong SL, Tai JA, Poh HM, Yao F, Sia YY, Lim EKH, Takano AM, Tan DS, Javed A, Hillmer AM (2020) Experimental and bioinformatics considerations in cancer application of single cell genomics. Comput Struct Biotechnol J. 19:343-354.
  • Heydt C, Rehker J, Pappesch R, Buhl T, Ball M, Siebolts U, Haak A, Lohneis P, Büttner R, Hillmer AM, Merkelbach-Bruse S (2020) Analysis of tumor mutational burden: correlation of five large gene panels with whole exome sequencing. Sci Rep. 10:11387.
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  • Chen J, Zhang T, Yang H, Teo ASM, Amer LB, Sherbaf FG, Tan CQ, Alvarez JJS, Lu B, Lim JQ, Takano A, Nahar R, Lee YY, Phua CZJ, Chua KP, Suteja L, Chen PJ, Chang MM, Koh TPT, Ong BH, Anantham D, Hsu AAL, Gogna A, Too CW, Aung ZW, Lee YF, Wang L, Lim TKH, Wilm A, Choi DPS, Ng PY, Toh CK, Lim WT, Ma S, Lim B, Liu J, Tam WL, Skanderup AMJ, Yeong JPS, Tan EH, Creasy C, Tan DSW*, Hillmer AM*, Zhai W*. (2020) Genomic landscape and ethnic specificity of lung adenocarcinoma in Asia. Nat Genet 52:177-186
  • Wang Z, Yip LY, Lee JHJ, Wu Z, Chew HY, Chong PKW, Teo CC, Ang HY, Peh KLE, Yuan J, Ma S, Choo LSK, Basri N, Jiang X, Yu Q, Hillmer AM, Lim WT, Lim TKH, Takano A, Tan EH, Tan DSW, Ho YS, Lim B, Tam WL (2019) Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 25:825-837
  • Kong SL, Li H, Tai JA, Courtois ET, Poh HM, Lau DP, Haw YX, Iyer NG, Tan DSW, Prabhakar S, Ruff D, Hillmer AM (2019) Concurrent Single-Cell RNA and Targeted DNA Sequencing on an Automated Platform for Comeasurement of Genomic and Transcriptomic Signatures. Clin Chem 65:272-281
  • Simoni Y, Becht E, Fehlings M, Loh CY, Koo S-L, Teng KWW, Yeong JPS, Nahar R, Zhang T, Kared H, Duan K, Ang N, Podinger M, Lee YY, Larbi A, Khng AJ, Tan E, Fu D, Mathew R, Teo M, Lim WT, Toh CK, Ong BH, Koh T, Hillmer AM, Takano A, Lim TKH, Tan EH, Weiwei Z, Tan ESW, Tan IB, Newell EW (2018) Bystander CD8+ T cells are abundant in human tumour infiltrates and lack expression of CD39. Nature 557:575-579
  • Nahar R, Zhai W, Zhang T, Takano A, Khng AJ, Lee YY, Liu X, Lim CH, Koh TPT, Aung Z, Lim TKH, Veeravalli L, Yuan J, Teo ASM, Chan CX, Poh HM, Chua IML, Liew AA, Lau DPX, Kwang XL, Toh CK, Lim WT, Lim B, Tam WL, Tan E-H, Hillmer AM#, Tan DSW# (2018) Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat Commun 9:216 (#corresponding author)
  • Li H, Courtois ET, Sengupta D, Tan Y, Chen KH, Goh JJL, Kong SL, Chua C, Hon LK, Tan WS, Wong M, Choi PJ, Wee LJK, Hillmer AM, Tan IB, Robson P, Prabhakar S (2017) Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat Genet 49:708-718
  • Chew EGY, Lim TC, Leong MF, Liu X, Sia YY, Leong ST, Yan-Jiang BC, Stoecklin C, Borhan R, Heilmann-Heimbach S, Nothen MM, Viasnoff V, Shyh-Chang N, Wan ACA, Philpott MP, and Hillmer AM (2022). Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia. Exp Dermatol. doi:10.1111/exd.14536.
  • Janning M, Suptitz J, Albers-Leischner C, Delpy P, Tufman A, Velthaus-Rusik JL, Reck M, Jung A, Kauffmann-Guerrero D, Bonzheim I, Brandlein S, Hummel HD, Wiesweg M, Schildhaus HU, Stratmann JA, Sebastian M, Alt J, Buth J, Esposito I, Berger J, Togel L, Saalfeld FC, Wermke M, Merkelbach-Bruse S, Hillmer AM, Klauschen F, Bokemeyer C, Buettner R, Wolf J, Loges S, and National Network Genomic Medicine Lung C (2022). Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM). Ann Oncol. doi:10.1016/j.annonc.2022.02.225.
  • Kong SL, Liu X, Tan SJ, Tai JA, Phua LY, Poh HM, Yeo T, Chua YW, Haw YX, Ling WH, Ng RCH, Tan TJ, Loh KWJ, Tan DS, Ng QS, Ang MK, Toh CK, Lee YF, Lim CT, Lim TKH, Hillmer AM, Yap YS, and Lim WT (2021). Complementary Sequential Circulating Tumor Cell (CTC) and Cell-Free Tumor DNA (ctDNA) Profiling Reveals Metastatic Heterogeneity and Genomic Changes in Lung Cancer and Breast Cancer. Front Oncol11, 698551. doi:10.3389/fonc.2021.698551.
  • Li J, Wu X, Schiffmann L, MacVicar T, Zhou C, Wang Z, Li D, Camacho OV, Heuchel R, Odenthal M, Hillmer A, Quaas A, Zhao Y, Bruns CJ, and Popp FC (2021). IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth. Cancers (Basel)13. doi:10.3390/cancers13215338.
  • Tan JHJ, Kong SL, Tai JA, Poh HM, Yao F, Sia YY, Lim EKH, Takano AM, Tan DS, Javed A, and Hillmer AM (2021). Experimental and bioinformatics considerations in cancer application of single cell genomics. Comput Struct Biotechnol J19, 343-354. doi:10.1016/j.csbj.2020.12.021.
  • Hoppe S, Jonas C, Wenzel MC, Velazquez Camacho O, Arolt C, Zhao Y, Buttner R, Quaas A, Plum PS, and Hillmer AM (2021). Genomic and Transcriptomic Characteristics of Esophageal Adenocarcinoma. Cancers (Basel)13. doi:10.3390/cancers13174300.
  • Perne C, Peters S, Cartolano M, Horpaopan S, Grimm C, Altmüller J, Sommer AK, Hillmer AM, Thiele H, Odenthal M, Möslein G, Adam R, Sivalingam S, Kirfel J, Schweiger MR, Peifer M, Spier I, Aretz S. Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis. PLoS One. 2021 Nov 29;16(11):e0259185.
  • Kramer M, Plum PS, Velazquez Camacho O, Folz-Donahue K, Thelen M, Garcia-Marquez I, Wolwer C, Busker S, Wittig J, Franitza M, Altmuller J, Loser H, Schlosser H, Buttner R, Schroder W, Bruns CJ, Alakus H, Quaas A, Chon SH, and Hillmer AM (2020). Cell type-specific transcriptomics of esophageal adenocarcinoma as a scalable alternative for single cell transcriptomics. Mol Oncol 14, 1170-84.
  • Zhou C, Fan N, Liu F, Fang N, Plum PS, Thieme R, Gockel I, Gromnitza S, Hillmer AM, Chon SH, Schlosser HA, Bruns CJ, and Zhao Y (2020). Linking Cancer Stem Cell Plasticity to Therapeutic Resistance-Mechanism and Novel Therapeutic Strategies in Esophageal Cancer. Cells 9.
Prof. Dr. Axel Hillmer CMMC Cologne
Prof. Dr. Axel Hillmer

Institute for General Pathology and Pathological Anatomy

CMMC - PI - assoc. RG 09

 

+49 221 478 85643

Institute for General Pathology and Pathological Anatomy

Joseph-Stelzmann-Str. 26

50931 Cologne

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Publications - Axel Hillmer

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