ERBB3 and IGF1R Signaling Are Required for Nrf2-Dependent Growth in KEAP1-Mutant Lung Cancer

Mutations in and (encoding the protein Nrf2) are prevalent in both adeno and squamous subtypes of non-small cell lung cancer, as well as additional tumor indications. The consequence of these mutations is stabilized Nrf2 and chronic induction of a battery of Nrf2 target genes. We show that knockdown...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2019-10, Vol.79 (19), p.4828-4839
Main Authors: Vartanian, Steffan, Lee, James, Klijn, Christiaan, Gnad, Florian, Bagniewska, Maria, Schaefer, Gabriele, Zhang, Donglu, Tan, Jenille, Watson, Sara A, Liu, Liling, Chen, Honglin, Liang, Yuxin, Watanabe, Colin, Cuellar, Trinna, Kan, David, Hartmaier, Ryan J, Lau, Ted, Costa, Michael R, Martin, Scott E, Merchant, Mark, Haley, Benjamin, Stokoe, David
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - metabolism
Carcinoma, Non-Small-Cell Lung - pathology
Cell Line, Tumor
Cell Proliferation - physiology
Heterografts
Humans
Kelch-Like ECH-Associated Protein 1 - genetics
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Mice
Mutation
NF-E2-Related Factor 2 - metabolism
Receptor, ErbB-3 - metabolism
Receptor, IGF Type 1 - metabolism
Signal Transduction - physiology
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Summary:Mutations in and (encoding the protein Nrf2) are prevalent in both adeno and squamous subtypes of non-small cell lung cancer, as well as additional tumor indications. The consequence of these mutations is stabilized Nrf2 and chronic induction of a battery of Nrf2 target genes. We show that knockdown of Nrf2 caused modest growth inhibition of cells growing in two-dimension, which was more pronounced in cell lines expressing mutant KEAP1. In contrast, Nrf2 knockdown caused almost complete regression of established KEAP1-mutant tumors in mice, with little effect on wild-type (WT) KEAP1 tumors. The strong dependency on Nrf2 could be recapitulated in certain anchorage-independent growth environments and was not prevented by excess extracellular glutathione. A CRISPR screen was used to investigate the mechanism(s) underlying this dependence. We identified alternative pathways critical for Nrf2-dependent growth in KEAP1-mutant cell lines, including the redox proteins thioredoxin and peroxiredoxin, as well as the growth factor receptors IGF1R and ERBB3. IGF1R inhibition was effective in KEAP1-mutant cells compared with WT, especially under conditions of anchorage-independent growth. These results point to addiction of KEAP1-mutant tumor cells to Nrf2 and suggest that inhibition of Nrf2 or discrete druggable Nrf2 target genes such as IGF1R could be an effective therapeutic strategy for disabling these tumors. SIGNIFICANCE: This study identifies pathways activated by Nrf2 that are important for the proliferation and tumorigenicity of KEAP1-mutant non-small cell lung cancer.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-18-2086