Publications by authors named "Liam Baird"
Background: The development and clinical success of KRAS inhibitors was a landmark achievement in anti-cancer drug development, as oncogenic KRAS had long been considered an intractable therapeutic target. Patients with KRAS mutant lung cancers frequently present with co-mutations in the KEAP1-NRF2 pathway, and because genetic activation of NRF2 results in resistance to all current anti-cancer therapies, we were motivated to explore how aberrant activation of NRF2 impacts the clinical response to KRAS inhibitors.
Methods: A broad range of techniques, including genetic knockouts, scRNA-seq and surface plasmon resonance, were used to determine the effect of KRAS drugs on NRF2.
Constitutive activation of NRF2 provides a selective advantage to malignant tumour clones through the hijacking of the NRF2-dependent cytoprotective transcriptional program, which allows the cancer cells to survive and thrive in the chemically stressful tumour niche, whilst also providing resistance to anti-cancer drugs due to the upregulation of xenobiotic metabolizing enzymes and drug efflux pumps. Through a small-molecule epigenetic screen carried out in KEAP1 mutant lung cancer cells, in this study, we identified CCS1477 (Inobrodib) to be an inhibitor of the global NRF2-dependent transcription program. Mechanistically, CCS1477 is able to repress NRF2's cytoprotective response through the inhibition of its obligate transcriptional activator partner CBP/p300.
View Article and Find Full Text PDFIn esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity.
View Article and Find Full Text PDFArticle Synopsis
- - In the KEAP1-NRF2 system, KEAP1 detects oxidative and electrophilic stresses using unique bonds, raising questions about how these sensors work in living organisms and whether they sense different types of stress through similar or distinct mechanisms.
- - Research utilizing genetically modified mice indicated that while a lack of certain selenoproteins leads to heightened NRF2 activation, removing critical KEAP1 cysteine residues prevents this activation, suggesting differentiated roles in stress sensing.
- - The study found that a single modification in KEAP1 can substantially impact its function and identified human genetic variations that affect oxidative stress sensors, but not electrophilic sensors, emphasizing the KEAP1 system's reliability in responding to oxidative stress.
Article Synopsis
- Whole blood transcriptome analysis offers valuable insights for medical research, primarily due to easy sample collection and the detailed information it provides about gene expression influenced by factors like age and gender.
- A study was conducted on 576 participants from the Tohoku Medical Megabank, stratifying by age (20-30s and 60-70s) and gender, including pregnant women, to analyze RNA sequencing data and investigate gene expression differences.
- Findings revealed associations between gene expression and age/gender differences, as well as the impact of immune response status (neutrophil-to-lymphocyte ratio) on gene diversity, resulting in a significant data set for future research in the Japanese population.
Article Synopsis
- Activating mutations in the KEAP1-NRF2 pathway are common in human cancers, leading to increased tumor aggressiveness and resistance to chemotherapy and immune checkpoint inhibitors.
- NRF2 activation helps cancer cells escape immune detection through a process called immunoediting, which involves decreased antigen presentation and reduced expression of NK cell activating ligands.
- Consequently, NRF2-activated cancers often create an "immunologically cold" tumor microenvironment that hinders immune system attack and promotes tumor progression.
Article Synopsis
- The KEAP1-NRF2 pathway is crucial for protecting cells from oxidative stress, but when overactive, it can allow damaged cells to survive, which can be harmful.
- Researchers have identified a specific gene program named the NRF2-induced secretory phenotype (NISP) that NRF2 activates in diseased states, promoting the secretion of signals that attract immune cells to damaged areas.
- In mouse models of liver disease, the NISP helps recruit immune cells to eliminate severely damaged cells, thus preventing the potentially negative effects of cell survival, and acting as a tumor suppressor.
Article Synopsis
- The KEAP1-NRF2 pathway is crucial for the body's response to oxidative stress, and its mutations are commonly found in aggressive cancers that resist treatment.
- These cancers are known for their poor prognosis and resistance to existing therapies, prompting a need for new treatment methods.
- The review explores how NRF2 hyperactivation leads to tumor resistance to therapy and suggests that using a synthetic lethal strategy with prodrugs could effectively target these challenging tumors.
Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity.
Free Radic Biol Med
July 2022
The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy.
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- * Researchers tested various chemotherapy drugs on normal and Keap1 knockout cells to find those more effective against cancer cells with high Nrf2 levels, identifying mitomycin C as particularly toxic to these cells.
- * Mitomycin C's enhanced effectiveness is linked to specific NRF2 target genes, making it a promising drug repurposing option for treating tumors with abnormal NRF2 activity, especially since it is already approved for clinical use.
Article Synopsis
- - Activating mutations in KEAP1-NRF2 are common in aggressive tumors, particularly in the lung, esophagus, and liver, leading to poor survival rates and resistance to treatments.
- - There's a critical need for therapies targeting NRF2, as no approved drugs currently inhibit its function, prompting researchers to develop a new screening method to identify NRF2-selective compounds.
- - Three geldanamycin-derived compounds were found to selectively kill NRF2-active cells; these have potential for repurposing in clinical settings since they have already been tested in trials.
Article Synopsis
- The KEAP1-NRF2 pathway is essential for protecting cells from oxidative and electrophilic stresses, acting as a primary defense system.
- Normally, KEAP1 keeps NRF2 in check by marking it for degradation, but when stress occurs, NRF2 can evade this process, accumulate, and then activate genes that counteract stress.
- Recent research shows that KEAP1's different stress sensors integrate various signals to regulate NRF2, making its activation vital for managing many diseases, suggesting that targeting NRF2 could lead to new treatments for a variety of health issues.
The Keap1-Nrf2 system plays a central role in the oxidative stress response; however, the identity of the reactive oxygen species sensor within Keap1 remains poorly understood. Here, we show that a Keap1 mutant lacking 11 cysteine residues retains the ability to target Nrf2 for degradation, but it is unable to respond to cysteine-reactive Nrf2 inducers. Of the 11 mutated cysteine residues, we find that 4 (Cys226/613/622/624) are important for sensing hydrogen peroxide.
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- Nrf2 is important for regulating how cells deal with oxidative stress, and its overactivation due to the loss of Keap1 can lead to severe health issues in mice.
- Removing Nrf2 from the oesophagus in Keap1-null mice allows them to survive but leads to kidney problems, such as polyuria and hydronephrosis, due to lower levels of aquaporin 2, which is crucial for water reabsorption.
- The study indicates that controlling Nrf2 activity during development is essential for kidney health and suggests that specific ablation of Nrf2 could help create animal models to explore new functions of this protein.
Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins.
View Article and Find Full Text PDFAbsolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells.
Mol Cell Biol
December 2016
Article Synopsis
- Nrf2 is a key transcription factor that helps cells respond to oxidative and electrophilic stress, while Keap1 regulates its activity through degradation and acts as a sensor for such stresses.
- Researchers assessed the levels of Nrf2, Keap1, and Cul3 proteins in various murine cell lines, finding that Nrf2 levels were normally lower than Keap1 and Cul3, but increased significantly when exposed to stress.
- During stress, the increase in Nrf2 did not affect the levels or interactions of Keap1 and Cul3, indicating that Nrf2 regulation in response to stress relies on its activity rather than changes in the composition of the Nrf2-Keap1-Cul3 complex.*
Article Synopsis
- Nrf2 activation can help protect against cancer in animal models by promoting detoxification, but mutations in Nrf2 can also make human cells more aggressive by enhancing tumor growth.
- In a study using mice with high Nrf2 levels, it was found that these mice had fewer and smaller urethane-induced tumors due to improved detoxification of the chemical.
- However, when cancer cells from these mice were transplanted, they showed increased tumor growth, indicating that while Nrf2 activation can aid in cancer prevention, it may also boost the aggressiveness of established tumors, highlighting its complex role in cancer progression.
Article Synopsis
- * Nrf2 interacts with the protein Keap1 in a two-step cycle that alters its conformation, eventually stabilizing Nrf2 and allowing it to activate genes that defend against stress.
- * Recent research highlights Nrf2's involvement in metabolism and mitochondrial function, enhancing cellular respiration by supplying substrates and boosting fatty acid oxidation.
Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response.
Mol Cell Biol
January 2016
Article Synopsis
- The Keap1-Nrf2 system is crucial for protecting cells from oxidative and electrophilic stresses, utilizing specific cysteine residues in Keap1 as sensors.
- Researchers identified mutations in two cysteine residues (Cys273 and Cys288) that allow Keap1 to still repress Nrf2 while also analyzing their functionality.
- The study categorized chemical inducers of Nrf2 into four classes based on which cysteine residues they require, highlighting that Keap1 employs these residues both individually and together to react to various environmental stresses.
Article Synopsis
- Nrf2 is a transcription factor that controls the expression of protective enzymes and proteins involved in metabolism.
- Compounds that inhibit the Nrf2-Keap1 interaction could be used as treatments for diseases like neurodegenerative disorders and cancer.
- The study involves creating 1,4-diphenyl-1,2,3-triazole compounds that successfully disrupt the Nrf2-Keap1 interaction in lab tests and increase Nrf2-dependent gene expression.
Article Synopsis
- NRF1 is crucial for regulating genes involved in protein degradation, metabolism, and transport, as shown by disruptions causing severe defects in mice.
- The research developed a special reporter system to identify compounds that could boost NRF1 activity, leading to the discovery of two compounds that increased luciferase activity.
- One of the compounds, T1-20, not only enhanced luciferase activity significantly but also increased NRF1 protein levels in mouse liver, marking a breakthrough in NRF1-specific inducers.
Article Synopsis
- Researchers are exploring the use of anti-hypoxic stress enzymes and proteins as a treatment strategy to slow down diseases related to the heart, kidneys, or brain suffering from low oxygen levels.
- To identify effective compounds that activate the HIF-α system and simulate hypoxic conditions, a high-throughput screening (HTS) system was created to directly measure HIF-α transcription.
- The new system, called SKN:HRE-NLuc, uses an advanced luciferase for better performance and is set up for efficient screening of potential therapeutics.
Article Synopsis
- Liver-specific knockout of Nrf1 in mice leads to the development of nonalcoholic steatohepatitis, characterized by significant lipid accumulation in the liver and altered fatty acid composition.
- Inducing Nrf1 knockout with 3-methylcholanthrene results in increased levels of glutathione and upregulation of the xCT antiporter gene, suggesting a complex role for Nrf1 in regulating antioxidant defenses.
- Nrf1's regulatory function is critical in managing both fatty acid metabolism and the balance of cysteine content in liver cells, indicating its involvement in a larger stress response mechanism.
Article Synopsis
- The transcription factor Nrf2 and its regulator Keap1 control nearly 500 protective genes, with Keap1 targeting Nrf2 for degradation until certain inducers, like phytochemicals from cruciferous vegetables, prevent this.
- The article highlights sulforaphane, an isothiocyanate that activates Nrf2 by interacting with Keap1 and inducing a reaction that prevents Nrf2's degradation.
- A new FRET-based method combined with multiphoton FLIM is used to study the dynamics of the Keap1-Nrf2 complex and the cyclic model of Keap1-mediated Nrf2 degradation, discussing its implications for physiological balance and tumor biology.
Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex.
Proc Natl Acad Sci U S A
September 2013
Article Synopsis
- Nrf2 is a key transcription factor responsible for activating protective genes, and its regulation is influenced by Keap1, which typically targets Nrf2 for degradation.
- The study developed a new imaging technique to observe the interaction between Nrf2 and Keap1 at the single-cell level, revealing a dynamic interaction cycle between the two proteins.
- The findings suggest a model called "cyclic sequential attachment and regeneration," showing how Nrf2 can rapidly respond to changes in the environment without being immediately degraded.