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

Abstract

Mutations in KEAP1 and NFE2L2 (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 KEAP1mutant 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.

Integrative omics analysis identifies subtypes with therapeutic implications in lung adenocarcinoma harboring KEAP1/NFE2L2

“…The pathway analyses of this study also revealed that PI3K/Akt pathway was enriched in the P2 subgroup. Vartanian et al identi ed alternative pathways critical for NFE2L2-dependent growth in KEAP1-mutant cell lines, including IGF1R [33]. The ndings in this study suggested that inhibitors of IGF1R signaling were effective in the C2 subtype.…”

Aptamer‐SH2 superbinder‐based targeted therapy for pancreatic ductal adenocarcinoma

“…As XQ‐2d‐His‐SH2 CM‐(Arg)9 and His‐SH2 CM‐(Arg)9 exhibited similar pY‐binding and inhibitory ability in vitro as previously identified in Figure 2G, we utilized His‐SH2 CM‐(Arg)9 to investigate whether SH2 superbinder could block signal transduction in pY‐related pathways. Dysregulation in activity of EGFR, IGF‐1R, and VEGFR is highly correlated with a lot of cancers 54–56 . The enhanced affinity between SH2 superbinder and the pY implied that they may function as an inhibitor of pY‐based signaling pathways.…”

“…Dysregulation in activity of EGFR, IGF-1R, and VEGFR is highly correlated with a lot of cancers. [54][55][56] The enhanced affinity between SH2 superbinder and the pY implied that they may function as an inhibitor of pY-based sig-naling pathways. To test this hypothesis, we incubated the PANC-1 WCLs with His-SH2 CM-(Arg)9, His-SH2 Wt-(Arg)9, and His-(Arg)9, respectively.…”

Role of NRF2 in Lung Cancer

“…Li et al described that EZH2 (enhancer of zeste homolog 2) inhibits lung cancer growth both in vitro and in vivo, and it does so by binding and repressing the NFE2L2 promoter [125]. Additionally, tyrosine kinase receptors, such as insulin-like growth factor 1 receptor (IGF1R) and erb-B2 receptor tyrosine kinase 3 (ERBB3), were recently discovered to be also important for KEAP1-mutant lung cell growth [126]. Krall et al showed that KEAP1 loss is involved in the resistance of NSCLC cell lines with mutations in EGFR, ALK, B-RAF and K/N-RAS to selective inhibitors of these kinases [127].…”