We further identified an NRF2-regulated metabolic gene signature (NRMGS) by correlating the microarray data with lung adenocarcinoma RNA-Seq gene expression data from The Cancer Genome Atlas followed by qRT-PCR validation, and finally showed that higher expression of the signature conferred a poor prognosis in 8 independent NSCLC cohorts.
We demonstrate the discovery and validation of ML385 as a novel and specific NRF2 inhibitor and conclude that targeting NRF2 may represent a promising strategy for the treatment of advanced NSCLC.
Using multiple isogenic non-small cell lung cancer (NSCLC) cell lines, we observed a reduction of Nrf2 protein and activity in a prometastatic mesenchymal cell state and increased reactive oxygen species.
Unexpectedly, stable knockdown of KEAP1 by lentiviral shRNA sensitized three independent NSCLC cell lines (A549, HTB-178, and HTB-182) to multiple chemotherapeutic agents, including arsenic trioxide (As(2)O(3)), etoposide, and doxorubicin, despite moderately increased NRF2 levels.
Unexpectedly, stable knockdown of KEAP1 by lentiviral shRNA sensitized three independent NSCLC cell lines (A549, HTB-178, and HTB-182) to multiple chemotherapeutic agents, including arsenic trioxide (As(2)O(3)), etoposide, and doxorubicin, despite moderately increased NRF2 levels.
To clarify metabolic features of NRF2-activated lung cancers, we conducted targeted metabolomic (T-Met) and global metabolomic (G-Met) analyses of non-small-cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses.
Thus, a substantial fraction of human NSCLCs activates an NRF2-dependent transcriptional program that regulates serine and glycine metabolism and is linked to clinical aggressiveness.
This study demonstrates that the NRF2 pathway may serve as a therapeutic target in NSCLC, and ginseng compounds may be effective for the treatment of this disease.
The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1.
Taken together, our results indicate that the Nestin-Keap1-Nrf2 axis regulates cellular redox homeostasis and confers oxidative stress resistance in NSCLC.
Specifically, Nrf2 plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and we found that combination of CP-673451 and cisplatin produced a synergistic anticancer effect and substantial ROS production in vitro.
SIGNIFICANCE: This study identifies pathways activated by Nrf2 that are important for the proliferation and tumorigenicity of KEAP1-mutant non-small cell lung cancer.
Samples of human non-small cell lung cancer (NSCLC) were used to correlate MOF with clinicopathological parameters and NF-E2-related factor 2 (Nrf2) downstream genes.
Recently, somatic mutations that activate NFE2L2, including mutations in <i>NFE2L2, KEAP1</i>, or <i>CUL3</i>, have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC).
Our findings suggest that NRF2 signaling plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and provides a rationale for using NRF2 as a specific biomarker for predicting which patients will be most likely to benefit from platinum-based treatment.