A phosphoglycerate mutase 1 allosteric inhibitor restrains TAM-mediated colon cancer progression.

Colorectal cancer (CRC) is a prevalent malignant tumor often leading to liver metastasis and mortality. Despite some success with PD-1/PD-L1 immunotherapy, the response rate for colon cancer patients remains relatively low. This is closely related to the immunosuppressive tumor microenvironment mediated by tumor-associated macrophages (TAMs).

Dependence of NPPS creates a targetable vulnerability in RAS-mutant cancers.

RAS is the most frequently mutated oncoprotein for cancer driving. Understanding of RAS biology and discovery of druggable lynchpins in RAS pathway is a prerequisite for targeted therapy of RAS-mutant cancers. The recent identification of KRAS inhibitor breaks the "undruggable" curse on RAS and has changed the therapy paradigm of KRAS-mutant cancers.

GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma.

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells.

Erratum: Aldehyde dehydrogenase 1A1 confers erlotinib resistance via facilitating the reactive oxygen species-reactive carbonyl species metabolic pathway in lung adenocarcinomas: Erratum.

[This corrects the article DOI: 10.7150/thno.35729.

A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma.

Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated.

Targeting AKR1B1 inhibits glutathione de novo synthesis to overcome acquired resistance to EGFR-targeted therapy in lung cancer.

Acquired resistance represents a bottleneck to molecularly targeted therapies such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. A deeper understanding of resistance mechanisms can provide insights into this phenomenon and help to develop additional therapeutic strategies to overcome or delay resistance. Here, we identified a pharmacologically targetable metabolic mechanism that drives resistance to EGFR TKIs in lung cancer cell lines and patient-derived xenograft mice.

Erratum: Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase: Erratum.

[This corrects the article DOI: 10.7150/thno.23177.

NRF2-GPX4/SOD2 axis imparts resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer cells.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer (NSCLC), but acquired resistance limits their clinical application. NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy. In this study, we investigated the role of NRF2 in resistance to EGFR-TKIs.

Development and validation of a rapid, robust and sensitive UPLC-QQQ-MS/MS method for simultaneous quantification of GSH metabolism in lung cancer cells.

Changes in cellular metabolism accompany tumor therapeutic resistance. Metabolite concentrations specifically reflect the cellular state. Glutathione (GSH) metabolism maintains the redox homeostasis while also confers therapeutic resistance to cancer cells.

HKB99, an allosteric inhibitor of phosphoglycerate mutase 1, suppresses invasive pseudopodia formation and upregulates plasminogen activator inhibitor-2 in erlotinib-resistant non-small cell lung cancer cells.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of non-small cell lung cancer (NSCLC). HKB99 is a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1) that preferentially suppresses cell proliferation and induces more apoptosis in acquired erlotinib-resistant HCC827ER cells compared with its parental HCC827 cells. In this study we identified the molecular biomarkers for HKB99 response in erlotinib-resistant HCC827ER cells.

Aldehyde dehydrogenase 1A1 confers erlotinib resistance via facilitating the reactive oxygen species-reactive carbonyl species metabolic pathway in lung adenocarcinomas.

Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) such as erlotinib is a major challenge to achieve an overall clinical benefit of the targeted therapy. Recently, aldehyde dehydrogenase 1 (ALDH1) induction has been found to render lung adenocarcinomas resistant to EGFR-TKIs, and targeting ALDH1A1 becomes a novel strategy to overcome resistance. However, the molecular mechanism underlying such effect remains poorly understood.

A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer.

Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization.

UPLC-MS-based metabolomics reveals metabolic dysregulation in ALDH1A1-overexpressed lung adenocarcinoma cells.

Introduction: Specific oncogenotypes can produce distinct metabolic changes in cancer. Recently it is considered that metabolic reprograming contributes heavily to drug resistance. Aldehyde dehydrogenase 1A1 (ALDH1A1), is overexpressed in drug resistant lung adenocarcinomas and may be the cause of acquired drug resistance.

[Effects of temperature and moisture on net ecosystem CO exchange over a meadow wetland in the Horqin, China].

Using the eddy covariance technique, the Bowen-ratio meteorological and soil monitoring system, we analyzed the CO flux dynamics and its responses to temperature and moisture over a meadow wetland in the Horqin during the growing season (from May to September) in 2016. The results showed that the accumulated net ecosystem CO exchange (NEE) was -766.18 g CO·m during the growing season.

Overcoming erlotinib resistance in EGFR mutation-positive lung adenocarcinomas through repression of phosphoglycerate dehydrogenase.

How to improve the efficacy and reverse the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of lung adenocarcinoma with EGFR-activating mutation. Phosphoglycerate dehydrogenase (PHGDH) is the key enzyme of serine biosynthesis over-expressed in various types of cancer including lung cancer. Elevated PHGDH expression is correlated with a worse overall survival in clinical lung adenocarcinoma patients.

Interleukin-6 identified as an important factor in hypoxia- and aldehyde dehydrogenase-based gefitinib adaptive resistance in non-small cell lung cancer cells.

Gefitinib resistance and relapse of the disease were the greatest challenges facing clinical therapy of non-small-cell lung cancer (NSCLC). Of note, regarding the hypoxia condition in solid tumor tissues , roles of hypoxia in gefitinib adaptive resistance and its association with lung cancer stem cells (LCSCs) have not been fully elucidated. In the present study, the role of hypoxia in gefitinib adaptive resistance and its association with aldehyde dehydrogenase (ALDH)-based LCSC gefitinib resistance were comparatively studied using RNA-sequencing (RNA-seq) technology.

Autocrine glutamatergic transmission for the regulation of embryonal carcinoma stem cells.

Glutamate behaves as the principal excitatory neurotransmitter in the vertebrate central nervous system and recently demonstrates intercellular signaling activities in periphery cancer cells. How the glutamatergic transmission is organized and operated in cancer stem cells remains undefined. We have identified a glutamatergic transmission circuit in embryonal carcinoma stem cells.

[Characteristics of surface energy fluxes over a sparse shrubland ecosystem in the farming-pastoral zone of the Loess Plateau, Northwest China].

Based on the energy flux and meteorological data during 2011-2012 over a sparse shrubland ecosystem in the farming-pastoral zone of the Loess Plateau, this study investigated the diurnal and seasonal variations of the energy balance components, and discussed the responses of the latent and sensible heat fluxes to different intensities of rainfall events. In addition, we identified the major environmental controlling factors on latent and sensible heat fluxes via correlation analysis. The results showed that the diurnal and seasonal variations of net radiation (Rn), sensible heat flux (H), latent heat flux (LE) and soil heat flux (G) all showed single-peak curves.