Synergy between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small-Cell Lung Cancer with an Altered Immune Microenvironment

Abstract

The lung presents a highly oxidative environment, which is tolerated through engagement of tightly controlled stress response pathways. A critical stress response mediator is the transcription factor nuclear factor erythroid-2-related factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major cancer driver. We demonstrate that inactivation of Keap1 and Pten in the mouse lung promotes adenocarcinoma formation. Notably, metabolites identified in the plasma of Keap1/Pten tumor-bearing mice indicate that tumorigenesis is associated with reprogramming of the pentose phosphate pathway. Furthermore, the immune milieu was dramatically changed by Keap1 and Pten deletion, and tumor regression was achieved utilizing immune checkpoint inhibition. Thus, our study highlights the ability to exploit both metabolic and immune characteristics in the detection and treatment of lung tumors harboring KEAP1/NRF2 pathway alterations.

Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases

“…47 Efforts that facilitate wide-scale implementation are currently underway. [48][49][50] For KRAS-mutant ADC, co-occurring deleterious TP53 mutations (357/1,006, 36% in our cohort) confer higher response rates to checkpoint blockade, while mutational inactivation of STK11 (8% in our cohort) promotes ICI resistance in patients and syngeneic murine models. For example, TP53, KRAS and KEAP1 mutations are associated with high TMB and high PD-L1 expression as well as benefit from ICI in lung ADC.…”

“…For example, TP53, KRAS and KEAP1 mutations are associated with high TMB and high PD-L1 expression as well as benefit from ICI in lung ADC. [48][49][50] For KRAS-mutant ADC, co-occurring deleterious TP53 mutations (357/1,006, 36% in our cohort) confer higher response rates to checkpoint blockade, while mutational inactivation of STK11 (8% in our cohort) promotes ICI resistance in patients and syngeneic murine models. 51 In our dataset, we observed a negative effect of STK11 mutations on benefit of NSCLC patients from immunotherapy, but a positive influence of KRAS/TP53 co-mutations ( Fig.…”

SdrA, an NADP(H)‐regenerating enzyme, is crucial for Coxiella burnetii to resist oxidative stress and replicate intracellularly

“…Following centrifugation, the clear upper aqueous phase was collected into a fresh microcentrifuge tube and dried in rotational vacuum concentrator (RVC‐2‐33; John Morris Scientific) with 30 μl of methanol added to the final drying step. The pulled point inserts were sealed in GC/LC vials and derivatised using methoxyamine (Sigma) and N,O‐bistrimethylsilyltrifluoroacetamide (BSTFA) containing 1% trimethylchlorosilane (TMCS; Thermo Scientific) before analysis of polar metabolites using the Shimadzu GC‐QQQ as described previously (Best et al, ; Masukagami et al, ).…”

“…To induce phase separation, the supernatant was adjusted to entific) before analysis of polar metabolites using the Shimadzu GC-QQQ as described previously (Best et al, 2018;Masukagami et al, 2017).…”

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

“…c) Phosphorylation and ubiquitination of various protein kinases. Direct phosphorylation of Ser40, Ser568, Degron domain and other unknown sites induced by phosphorylation of protein kinase C(PKC), mitogen‐activated protein kinase (MAPK), glycogen synthase kinase‐3 beta (GSK‐3 β ) and the phosphatidylinositol 3‐kinase pathway (PI3 K/AKT), etc., which closely related to Nrf2 activation; whereas phosphorylation at Ser215, Ser408 and Ser 577 of Nrf2 to restrict the activity of Nrf2 . d) Binding with other protein molecules.…”