Emerging strategies to overcome resistance to third-generation EGFR inhibitors

Shi, Kunyu; Wang, Guan; Pei, Junping; Zhang, Jifa; Wang, Jiaxing; Ouyang, Liang; Wang, Yuxi; Liu, Weimin

doi:10.1186/s13045-022-01311-6

Cited by 72 publications

(47 citation statements)

References 210 publications

(161 reference statements)

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“…Inhibiting phosphorylation of AKT1 can induce BV-2 microglia activation which leads to neuroinflammation ( Xiao et al, 2022 ). EGFR is one of the receptor proteins of the growth factor family, and participates in cell proliferation and signal transduction ( Shi et al, 2022 ). Inhibition of EGFR/MAPK signaling pathway could suppress microglia activation and reduce secondary damage related to neuroinflammation ( Qu et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer’s disease

Ren

Zhang

et al. 2022

Front. Neurosci.

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There is yet no effective drug for Alzheimer’s disease (AD) which is one of the world’s most common neurodegenerative diseases. The Qin-Zhi-Zhu-Dan Formula (QZZD) is derived from a widely used Chinese patent drug–Qing-Kai-Ling Injection. It consists of Radix Scutellariae, Fructus Gardeniae, and Pulvis Fellis Suis. Recent study showed that QZZD and its effective components played important roles in anti-inflammation, antioxidative stress and preventing brain injury. It was noted that QZZD had protective effects on the brain, but the mechanism remained unclear. This study aims to investigate the mechanism of QZZD in the treatment of AD combining network pharmacology approach with experimental validation. In the network pharmacology analysis, a total of 15 active compounds of QZZD and 135 putative targets against AD were first obtained. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were then applied to clarify the biological mechanism. The anti-inflammatory mechanism of QZZD was proved, and a synthetic pathway–TNFR1-ERK1/2-NF-κBp65 signaling pathway was obtained. On the basis of the above discoveries, we further validated the protective effects QZZD on neurons with an APP/PS1 double transgenic mouse model. Weight change of the mice was monitored to assess QZZD’s influence on the digestive system; water maze experiment was used for evaluating the effects on spatial learning and memory; Western blotting and immunohistochemistry analysis were used to detect the predicted key proteins in network pharmacology analysis, including Aβ, IL-6, NF-κBp65, TNFR1, p-ERK1/2, and ERK1/2. We proved that QZZD could improve neuroinflammation and attenuate neuronal death without influencing the digestive system in APP/PS1 double transgenic mice with dementia. Combining animal pharmacodynamic experiments with network pharmacology analysis, we confirmed the importance of inflammation in pathogenesis of AD, clarified the pharmacodynamic characteristics of QZZD in treating AD, and proved its neuroprotective effects through the regulation of TNFR1-ERK1/2-NF-κBp65 signaling pathway, which might provide reference for studies on treatment of AD in the future.

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Section: Discussionmentioning

confidence: 99%

Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer’s disease

Ren

Zhang

et al. 2022

Front. Neurosci.

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“…These limitations are mainly due to the nature of primary and emerging secondary escape mutations in the receptor (EGFR T790M ) and acquired resistance as well as pathway mutations e.g. JAK2 V617F (EPOR/TPOR) that lead to constitutively over activation and dysregulation with detrimental outcome for patients (Chan et al, 2017; Glassman et al, 2022; Kumar et al, 2020; Shi et al, 2022).…”

Section: Mainmentioning

confidence: 99%

Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox

Siepe

Picton

Garcia

2022

Preprint

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In recent years, targeted protein degradation (TPD) of plasma membrane proteins by hijacking the ubiquitin proteasome system (UPS) or the lysosomal pathway have emerged as novel therapeutic avenues in drug development to address and inhibit canonically difficult targets. While TPD strategies have been successful to target cell surface receptors, these approaches are limited by the availability of suitable binders to generate heterobifunctional molecules. Here, we present the development of a nanobody (VHH) based degradation toolbox termed REULR (Receptor Elimination by E3 Ubiquitin Ligase Recruitment). We generated human and mouse cross-reactive nanobodies against 5 transmembrane PA-TM-RING type E3 Ubiquitin Ligases (RNF218, RNF130, RNF167, RNF43, ZNRF3) covering a broad range and selectivity of tissue expression with which we characterized expression in human and mouse cell lines and immune cells (PBMCs). We demonstrate that heterobifunctional REULR molecules can enforce transmembrane E3 ligase interaction with a variety of disease relevant target receptors (EGFR, EPOR, PD-1) by induced proximity resulting in effective membrane clearance of the target receptor at varying levels. In addition, we designed E3 Ligase self-degrading molecules, "fratricide" REULRs (RNF128, RNF130, RENF167, RNF43, ZNRF3), that allow downregulation of one or several E3 Ligases from the cell surface and consequently modulate receptor signaling strength. REULR molecules represent a VHH-based, modular and versatile "mix and match" targeting strategy for facile modulation of cell surface proteins by induced proximity to transmembrane PA-TM-RING E3 ligases.

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“…Several studies have suggested that acquired resistance mechanisms to EGFR inhibitors involve the compensatory activation of redundant signalling pathways that share effectors or downstream modulators of the EGFR signalling cascade, thus bypassing EGFR inhibition. Different pathways can serve as alternative routes for reactivation of signalling downstream of inhibited EGFR, including MET, IGF-1R, PI3K-AKT-mTOR, BRAF/RAS and Wnt signalling pathways (39)(40)(41)(42), all able to sustain cell survival, proliferation, migration, and epithelialmesenchymal transition (EMT). Therefore, we downloaded the scRNA-seq dataset published by Aissa et al ( 27) comprising 1,044 PC9 lung cells (Figure 1G) that were subject to eleven days of consecutive erlotinib treatment and sequenced at six different time points (i.e., 0, 1, 2, 4, 9, and 11 days).…”

Section: Gifcf Package Overviewmentioning

confidence: 99%

Single-cell gene set enrichment analysis and transfer learning for functional annotation of scRNA-seq data

Pellecchia

Viscido

Franchini

et al. 2022

Preprint

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Although an essential step, the functional annotation of cells often proves particularly challenging in the analysis of single-cell transcriptional data. Several methods have been developed to accomplish this task. However, in most cases, these rely on techniques initially developed for bulk RNA sequencing or simply make use of marker genes identified from cell clustering followed by supervised annotation. To overcome these limitations and automatise the process, we have developed two novel methods, the single-cell gene set enrichment analysis (scGSEA) and the single cell mapper (scMAP). scGSEA combines latent data representations and gene set enrichment scores to detect coordinated gene activity at single-cell resolution. scMAP uses transfer learning techniques to re-purpose and contextualise new cells into a reference cell atlas. Using both simulated and real datasets, we show that scGSEA effectively recapitulates recurrent patterns of pathways' activity shared by cells from different experimental conditions. At the same time, we show that scMAP can reliably map and contextualise new single cell profiles on a breast cancer atlas we recently released. Both tools are provided in an effective and straightforward workflow providing a framework to determine cell function and significantly improve annotation and interpretation of scRNA-seq data.

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Emerging strategies to overcome resistance to third-generation EGFR inhibitors

Cited by 72 publications

References 210 publications

Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer’s disease

Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer’s disease

Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox

Single-cell gene set enrichment analysis and transfer learning for functional annotation of scRNA-seq data

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