ERBB3 and IGF1R signaling are required for Nrf2-dependent growth in KEAP1-mutant lung cancer.

ERBB3 and IGF1R signaling are required for Nrf2-dependent growth in KEAP1-mutant lung cancer. Cancer Res. 2019 Aug 15;: Authors: Vartanian S, Lee J, Klijn C, Gnad F, Bagniewska M, Schaefer G, Zhang D, Tan J, Watson SA, Liu L, Chen H, Liang Y, Watanabe C, Cuellar T, Kan D, Hartmaier RJ, Lau T, Costa MR, Martin SE, Merchant M, Haley B, Stokoe D Abstract Mutations in KEAP1 and NFE2L2 (encoding the protein Nrf2) are prevalent in both adenocarcinoma and squamous subtypes of non-small cell lung cancer. The consequence of these mutations is stabilized Nrf2 and chronic induction of several Nrf2 target genes. Here, downregulation of Nrf2 resulted in modest growth inhibition of cells growing in 2D; this was more pronounced in cell lines expressing mutant KEAP1. In contrast, downregulation of Nrf2 caused almost complete regression of established KEAP1-mutant tumors in mice, with little effect on wildtype (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. Using CRISPR screening we identified alternative pathways critical for Nrf2-dependent growth in KEAP1-mutant cell lines, including the redox proteins thioredoxin and peroxiredoxin, as well as growth factor receptors IGF1R and ERBB3. IGF1R inhibition was effective in KEAP1 mutant cells compared to WT, especially under conditions of anchorage-independent growth. Th...
Source: Genomics Proteomics ... - Category: Genetics & Stem Cells Authors: Tags: Cancer Res Source Type: research