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Jiayao Zhang,1– 3 Mingqing Zhang,1– 3 Xiaojing Wu,1,2 Haoren Jing,1– 3 Peiran Li,4 Wei Wang,5 Xi Guo,5 Zhenying Zhao,6 Siwei Zhu,1,2 Yijia Wang2 1School of Medicine, Nankai University, Tianjin, People’s Republic of China; 2Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China; 3Department of Colorectal Surgery, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China; 4Human Biology and Society, University of California, Los Angeles, CA, USA; 5TEDA Institute of Biological Sciences and Biotechnology, Nankai University, Tianjin, People’s Republic of China; 6Department of Pharmacy, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of ChinaCorrespondence: Siwei Zhu, School of Medicine, Nankai University, Tianjin, China; Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China, Email siweiz@nankai.edu.cn Yijia Wang, Tianjin Institute of Coloproctology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, Tianjin, People’s Republic of China, Email yijiawang₁980@nankai.edu.cnBackground: Cetuximab is an approved therapy for metastatic colorectal cancer (CRC) with wild-type RAS and BRAF; however, additional resistance mechanisms beyond genetic mutations remain poorly understood. Butyrate, a key metabolite produced by the gut microbiome and present in the circulatory system, has been reported to supply cellular energy and modulate the epidermal growth factor receptor (EGFR) downstream signaling pathway. However, whether butyrate affects the resistance to cetuximab is still unknown.Methods: In this work, Cell Counting Kit-8 (CCK-8) and colony formation assays were used to evaluate the efficacy of cetuximab. Glycolysis/oxidative phosphorylation (OXPHOS) Assay Kit was applied to assess metabolic activity. Human Phospho-Kinase Array and RNA sequencing were employed to screen targets of butyrate. Overexpression plasmids and short hairpin RNAs (shRNAs) targeting these molecules were transfected into cells for further validation. Subcutaneous tumor and pulmonary metastasis models were used for in vivo studies.Results: The findings showed that physiological concentrations of butyrate increased cetuximab resistance in KRAS wild-type cells only. Further investigation found that butyrate upregulated EGFR signaling through facilitating the binding reaction between epidermal growth factor (EGF) and EGFR. In parallel, butyrate activated AMP-activated protein kinase (AMPK)–wild-type p53-induced phosphatase 1 (Wip1) signaling, leading to suppression of p53 and p38 mitogen-activated protein kinase (p38 MAPK)-mediated pro-apoptotic signaling. These two mechanisms are the reason that butyrate attenuates the efficacy of cetuximab. Results of subcutaneous tumor and pulmonary metastasis models exhibited a similar conclusion to in vitro experiments.Conclusion: Butyrate reduces cetuximab efficacy in KRAS wild-type colorectal cancer through EGFR and AMPK–Wip1 signaling, and may represent a candidate predictive biomarker for treatment response.Keywords: cetuximab resistance, butyrate, colorectal cancer, EGFR signaling, AMPK/wip1 pathway

[This corrects the article DOI: 10.3389/fimmu.2024.1470449.].

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family.

Atherosclerosis is a chronic vascular disease characterized by the accumulation of cholesterol‐rich lipids within the intima of large and medium‐sized arteries. It is a leading cause of morbidity and mortality worldwide, contributing to the majority of myocardial infarctions and strokes. Ellagic acid (EA), a naturally occurring polyphenolic compound found in various plant species, exhibits promising potential in enhancing cholesterol metabolism and reducing the risk of atherosclerosis. However, the precise mechanisms and molecular targets underlying EA's cholesterol‐regulating effects remain poorly understood. In this study, we demonstrate that EA effectively binds to the epidermal growth factor receptor (EGFR), exhibiting a dissociation constant (Kd) of 4.33 × 10 −7  M and a binding energy of −7.1 kcal/mol. This binding activates EGFR and specifically engages the mitogen‐activated protein kinase (MAPK) pathway, leading to the upregulation of low‐density lipoprotein receptor (LDLR) expression in HepG2 cells. Furthermore, cetuximab, an EGFR‐blocking antibody, inhibits the LDLR upregulation induced by EA, confirming EGFR as a key target in the regulation of LDLR expression. To evaluate the in vivo effects of EA on atherosclerosis, we encapsulated EA within human serum albumin to form nanoparticles (EA‐NPs). This approach addresses poor water solubility and its tendency to convert into urolithin derivatives of EA following oral administration. In HepG2 cells, EA‐NPs significantly enhanced LDLR expression, accompanied by increased phosphorylation of EGFR and extracellular signal‐regulated kinase (ERK). In an ApoE − / − mouse model, EA‐NPs exhibited potent anti‐atherosclerotic effects mediated through the EGFR and MAPK pathways. Additionally, EA‐NPs reduced hepatic lipid accumulation and attenuated the formation of aortic plaques. In conclusion, EA and its nanoparticle formulation effectively impede the progression of atherosclerosis, underscoring their therapeutic potential. These findings provide a robust foundation for the development of EA‐based strategies as a viable daily therapeutic intervention for atherosclerosis management.

Background This study investigated the clinical implication of TNK2 expression in esophageal cancer patients’ cancer tissue samples. Methods The expression of TNK2 in esophageal cancer tissues and para‐carcinoma tissue was assessed with immunohistochemistry and Western blot analysis; besides, the proteins of CDC42, EGFR, and Akt were also analyzed. Then, Kaplan‐Meier survival curves of TNK2 protein expression level were assayed with 184 esophageal cancer patients from TCGA database. Moreover, with multiple linear regression analysis, we detected the correlations of TNK2 expression associated with tumor differentiation degree and metastasis status. Results It revealed that TNK2 was highly expressed in the cytoplasm of esophageal cancer tissues compared with para‐carcinoma tissue; besides, the proteins of CDC42, EGFR, and Akt were also up‐regulated in different levels of esophageal cancer tissues. However, there was no significant difference of the overall survival time of TNK2 protein expression in 184 esophageal cancer patients from TCGA database (p = 0.37). But, in the included study samples of our study, there was positive coefficience between TNK2 protein expression and differentiation degree in esophageal cancer with multiple linear regression analysis [R = 0.928, 95% confidence interval (0.085‐0.12)]. Conclusion Our results indicated that TNK2 was a potential diagnostic marker and promoted esophageal cancer progression through activating EGFR‐AKT signaling. The dependent linear equation was TNK2=0.103 + 0.042 (differentiation degree) ‐ 0.026 (metastasis status) with Multiple linear regression analysis, the coefficient of regression (R) was 0.928 of differentiation degree, ‐0.25 for status of metastasis, 95% confidence interval (0.085~0.12), p < 0.05, (X1: differentiation degree, X2: metastasis status).

Multicolor single-molecule tracking (SMT) provides a powerful tool to mechanistically probe molecular interactions in living cells. However, because of the limitations in the optical and chemical properties of currently available fluorophores and the multiprotein labeling strategies, intracellular multicolor SMT remains challenging for general research studies. Here, we introduce a practical method employing a nanopore-electroporation (NanoEP) technique to deliver multiple organic dye-labeled proteins into living cells for imaging. It can be easily expanded to three channels in commercial microscopes or be combined with other in situ labeling methods. Utilizing NanoEP, we demonstrate three-color SMT for both cytosolic and membrane proteins. Specifically, we simultaneously monitored single-molecule events downstream of EGFR signaling pathways in living cells. The results provide detailed resolution of the spatial localization and dynamics of Grb2 and SOS recruitment to activated EGFR along with the resultant Ras activation.

Epidermal growth factor receptor (EGFR) plays critical roles in cell proliferation, tumorigenesis, and anti-cancer drug resistance. Overexpression and somatic mutations of EGFR result in enhanced cancer cell survival. Therefore, EGFR can be a target for the development of anti-cancer therapy. Patients with cancers, including non-small cell lung cancers (NSCLC), have been shown to response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR antibodies. However, resistance to these anti-EGFR treatments has developed. Autophagy has emerged as a potential mechanism involved in the acquired resistance to anti-EGFR treatments. Anti-EGFR treatments can induce autophagy and result in resistance to anti-EGFR treatments. Autophagy is a programmed catabolic process stimulated by various stimuli. It promotes cellular survival under these stress conditions. Under normal conditions, EGFR-activated phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling inhibits autophagy while EGFR/rat sarcoma viral oncogene homolog (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) signaling promotes autophagy. Thus, targeting autophagy may overcome resistance to anti-EGFR treatments. Inhibitors targeting autophagy and EGFR signaling have been under development. In this review, we discuss crosstalk between EGFR signaling and autophagy. We also assess whether autophagy inhibition, along with anti-EGFR treatments, might represent a promising approach to overcome resistance to anti-EGFR treatments in various cancers. In addition, we discuss new developments concerning anti-autophagy therapeutics for overcoming resistance to anti-EGFR treatments in various cancers.

Interaction between the epidermal growth factor receptor (EGFR) and the insulin‐like growth factor receptor (IGF‐1R) has been well established in many cancer types. We investigated the effects of cetuximab (EGFR antibody) and IMC‐A12 (IGF‐1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). The effects of cetuximab and IMC‐A12 on cell viability and radiosensitivity were determined by clonogenic cell survival assay. Formation of nuclear γ‐H2AX and 53BP1 foci was monitored by immunofluorescence. Alterations in target signaling were analyzed by Western blots. In vivo tumor growth delay assay was performed to determine the efficacy of triple therapy with IMC‐A12, cetuximab, and RT. In vitro data showed that cetuximab differentially affected the survival and the radiosensitivity of HNSCC cells. Cetuximab suppressed DNA repair that was evident by the prolonged presence of nuclear γ‐H2AX and 53BP1 foci. IMC‐A12 did not have any effect on the cell survival. However, it increased the radiosensitivity of one of the cell lines. EGFR inhibition increased IGF‐1R expression levels and also the association between EGFR and IGF‐1R. Addition of IMC‐A12 to cetuximab did not increase the radiosensitivity of these cells. Tumor xenografts exhibited enhanced response to RT in the presence of either cetuximab or IMC‐A12. Concurrent treatment regimen failed to further enhance the tumor response to cetuximab and/or RT. Taken together our data suggest that concomitant inhibition of both EGFR and IGF‐1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT. We investigated the effects of cetuximab (epidermal growth factor receptor; EGFR antibody) and IMC‐A12 (insulin‐like growth factor receptor; IGF‐1R antibody) on the response of head and neck squamous cell carcinoma (HNSCC) to radiation therapy (RT). Our data suggest that concomitant inhibition of both EGFR and IGF‐1R pathways did not yield additional therapeutic benefit in overcoming resistance to RT.

Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics.

Non-small-cell lung cancer (NSCLC) is the most common lung cancer subtype and accounts for more than 80% of all lung cancer cases. Epidermal growth factor receptor (EGFR) phosphorylation by binding growth factors such as EGF activates downstream prooncogenic signaling pathways including KRAS-ERK, JAK-STAT, and PI3K-AKT. These pathways promote the tumor progression of NSCLC by inducing uncontrolled cell cycle, proliferation, migration, and programmed death-ligand 1 (PD-L1) expression. New cytotoxic drugs have facilitated considerable progress in NSCLC treatment, but side effects are still a significant cause of mortality. Gallic acid (3,4,5-trihydroxybenzoic acid; GA) is a phenolic natural compound, isolated from plant derivatives, that has been reported to show anticancer effects. We demonstrated the tumor-suppressive effect of GA, which induced the decrease of PD-L1 expression through binding to EGFR in NSCLC. This binding inhibited the phosphorylation of EGFR, subsequently inducing the inhibition of PI3K and AKT phosphorylation, which triggered the activation of p53. The p53-dependent upregulation of miR-34a induced PD-L1 downregulation. Further, we revealed the combination effect of GA and anti-PD-1 monoclonal antibody in an NSCLC-cell and peripheral blood mononuclear–cell coculture system. We propose a novel therapeutic application of GA for immunotherapy and chemotherapy in NSCLC.