EGFR Pathway Research Articles

Transcription factor PRRX1-activated ANXA6 facilitates EGFR-PKCα complex formation and enhances cisplatin sensitivity in bladder cancer

BackgroundTumor resistance to cisplatin represents a major clinical challenge, particularly in bladder cancer (BC). ANXA6 is a member of annexin family, and its role in cisplatin resistance remains unclear. This study explores ANXA6's role in promoting cisplatin sensitivity. MethodsBioinformatics analyses and clinical specimen verifications assessed the correlation between ANXA6 and cisplatin treatment. A series of assays, including CCK-8, clone formation assay, flow cytometry assays for reactive oxygen species (ROS) and apoptosis, and comet assays, were used to confirm ANXA6's role in enhancing cisplatin sensitivity and re-sensitizing resistant BC cells. Mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments elucidated ANXA6's role in enhancing PKCα/EGFR complex formation and inhibiting the EGFR pathway. ChIP-PCR and dual-luciferase assays determined PRRX1's regulatory role on ANXA6 transcription. Finally, the impact of ANXA6 in vivo was evaluated using xenograft models. ResultsBioinformatics analyses showed a significant correlation between ANXA6 expression and cisplatin sensitivity. In vitro and in vivo experiments confirmed that ANXA6 was a new target for cisplatin treatment. ANXA6 overexpression not only enhanced cell viability inhibition, DNA damage and apoptosis caused by cisplatin, but also re-sensitized cisplatin-resistant cells. Mechanistically, ANXA6 promotes PKCα/EGFR complex formation, inhibiting EGFR phosphorylation and downstream AKT and ERK1/2. Moreover, PRRX1 was identified as a transcription factor promoting ANXA6 expression, thereby augmenting the cytotoxic effects of cisplatin. ConclusionOur study reveals the mechanism by which ANXA6 enhances cisplatin sensitivity and re-sensitizes resistant cells. The roles of PRRX1 and ANXA6 in cisplatin resistance offer new therapeutic targets to overcome cisplatin resistance in clinical practice.

Abstract B036: Pathway repression in progression on osimertinib therapy in NSCLC via a comprehensive genomic and epigenomic circulating tumor DNA (ctDNA) assay

Abstract Background: Osimertinib is currently the most common precision therapy for patients with non- small cell lung cancer (NSCLC) with EGFR mutations. While it prolongs progression-free survival, resistance eventually develops in many, leading to disease progression. Somatic NGS has identified resistance mutations in the EGFR pathway and other oncogenes, but these account for only 40-45% of cases, suggesting non-genetic factors, such as epigenetic changes, may be involved. This study investigates the epigenetic landscape at diagnosis and progression on first- line osimertinib, focusing on cases with and without canonical resistance mutations. Methods: We defined two cohorts from GuardantINFORM, a clinico-genomics database, restricting to only patients with a test on the Guardant Infinity platform, a comprehensive blood-based NGS assay, that analyzes DNA sequence variants and performs extensive methylation profiling (∼15Mb) in >20,000 differentially methylated regions (DMRs) assessed for sample-specific methylation patterns. (A) Diagnosis Cohort: Comprised of 34 NSCLC patients with blood samples collected within six days prior to the initiation of first-line osimertinib therapy. (B) Progression Cohort: Comprised of 36 patients who were on first-line osimertinib therapy, with blood samples collected within 60 days of discontinuation. The progression cohort was further stratified based on the presence or absence of known resistance mutations identified through somatic variant analysis by Guardant360. Gene set enrichment analysis was conducted on these methylation profiles using the Reactome database to define pathway-level differences between the cohorts. Results: Pathway enrichment analysis in the diagnosis and progression cohorts found expected biological processes in NSCLC such as extracellular matrix organization, G- protein coupled receptor (GPCR) signaling, and FGFR pathways. Additionally, the progression cohort lacking canonical resistance mutations (n=23) exhibited unique enrichment in two specific pathways: Glucose-dependent Insulinotropic Polypeptide and Physiological Factors. These pathways include genes such as GATA4, which has been implicated in the epithelial- mesenchymal transition (EMT)—a process associated with transforming to a small cell phenotype, a known mechanism of resistance to EGFR inhibition, including osimertinib. Conclusion: This study demonstrates the utility of epigenetic profiling via liquid biopsies in uncovering non-genetic mechanisms underlying osimertinib resistance in advanced NSCLC. Identification of unique epigenetic pathways in progressing patients without canonical resistance mutations highlights the potential for discovering novel biomarkers of resistance. Further investigation into these findings may advance our understanding of resistance mechanisms across various cancer therapies, particularly for patients without identified genomic resistance, and inform clinical decision-making and trial design. Citation Format: Aaron Hardin, Leslie Bucheit, Amar Das, Craig Eagel, Helmy Eltoukhy. Pathway repression in progression on osimertinib therapy in NSCLC via a comprehensive genomic and epigenomic circulating tumor DNA (ctDNA) assay [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B036.

Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer: A Plausible Alliance to Enhance Cell Death

Background/Objectives: Head and neck cancer (HNC) is among the most common cancer types globally, with its incidence expected to increase significantly in the coming years. Oral squamous cell carcinoma (OSCC), the predominant subtype, exhibits significant heterogeneity and resistance to treatment. Current therapies, including surgery, radiation, and chemotherapy, often result in poor outcomes for advanced stages. Cetuximab, an EGFR inhibitor, is widely used but faces limitations. This study explores the combined inhibition of EGFR and mitotic proteins to enhance treatment efficacy. Methods: We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. The rationale is based on targeting EGFR-mediated survival pathways and the mitotic checkpoint, addressing multiple cell cycle phases and reducing resistance. Results: Our findings indicate that inhibiting MPS-1, Aurora-B, or KSP enhances Cetuximab’s therapeutic potential, promoting increased cancer cell death. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. Conclusions: This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC.

The Inhibitory Effect and Mechanism of the Histidine-Rich Peptide rAj-HRP from Apostichopus japonicus on Human Colon Cancer HCT116 Cells.

Colon cancer is a common and lethal malignancy, ranking second in global cancer-related mortality, highlighting the urgent need for novel targeted therapies. The sea cucumber (Apostichopus japonicus) is a marine organism known for its medicinal properties. After conducting a bioinformatics analysis of the cDNA library of Apostichopus japonicus, we found and cloned a cDNA sequence encoding histidine-rich peptides, and the recombinant peptide was named rAj-HRP. Human histidine-rich peptides are known for their anti-cancer properties, raising questions as to whether rAj-HRP might exhibit similar effects. To investigate whether rAj-HRP can inhibit colon cancer, we used human colon cancer HCT116 cells as a model and studied the tumor suppressive activity in vitro and in vivo. The results showed that rAj-HRP inhibited HCT116 cell proliferation, migration, and adhesion to extracellular matrix (ECM) proteins in vitro. It also disrupted the cytoskeleton and induced apoptosis in these cells. In vivo, rAj-HRP significantly inhibited the growth of HCT116 tumors in BALB/c mice, reducing tumor volume and weight without affecting the body weight of the tumor-bearing mice. Western blot analysis showed that rAj-HRP inhibited HCT116 cell proliferation and induced apoptosis by upregulating BAX and promoting PARP zymogen degradation. Additionally, rAj-HRP inhibited HCT116 cell adhesion and migration by reducing MMP2 levels. Further research showed that rAj-HRP downregulated EGFR expression in HCT116 cells and inhibited key downstream molecules, including AKT, P-AKT, PLCγ, P38 MAPK, and c-Jun. In conclusion, rAj-HRP exhibits significant inhibitory effects on HCT116 cells in both in vitro and in vivo, primarily through the EGFR and apoptosis pathways. These findings suggest that rAj-HRP has the potential as a novel targeted therapy for colon cancer.

Landscape of targeted therapies for lung squamous cell carcinoma.

Lung cancer, a common type of malignant neoplasm, has seen significant advancements in the treatment of lung adenocarcinoma (LUAD). However, the management of lung squamous cell carcinoma (LSCC) continues to pose challenges. Traditional treatment methods for LSCC encompass surgical resection, chemotherapy, and radiotherapy. The introduction of targeted therapy and immunotherapy has greatly benefited LSCC patients, but issues such as limited immune response rates and adverse reactions persist. Therefore, gaining a deeper comprehension of the underlying mechanisms holds immense importance. This review provides an in-depth overview of classical signaling pathways and therapeutic targets, including the PI3K signaling pathway, CDK4/6 pathway, FGFR1 pathway and EGFR pathway. Additionally, we delve into alternative signaling pathways and potential targets that could offer new therapeutic avenues for LSCC. Lastly, we summarize the latest advancements in targeted therapy combined with immune checkpoint blockade (ICB) therapy for LSCC and discuss the prospects and challenges in this field.

TNO155 is a selective SHP2 inhibitor to target PTPN11-dependent oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is known to be driven by multiple intricated receptor tyrosine kinases (RTKs) including EGFR, PI3K/AKT and MAPK signaling pathways. However, whilst targeting EGFR with cetuximab has been approved for the treatment of OSCC, other single-agent inhibitors of the RTKs have shown modest effects in improving survival. From the genome-wide CRISPR/Cas9 screen on 21 OSCC cell lines, we have identified PTPN11 among the top essential genes in OSCC. PTPN11 encodes for SHP2, a phosphatase that acts as a master signal transducer, downstream of various RTKs. Although PTPN11 overexpression has been reported in OSCC, little is known about its role as an essential gene for OSCC survival and its potential as a therapeutic target. Herein, we confirmed that PTPN11 is an essential gene in OSCC where its deletion significantly impacted cell survival. We evaluated three SHP2 inhibitors on 21 OSCC cell lines and found TNO155 to be significantly associated with CRISPR dependency score. We showed that TNO155 caused dose-dependent suppression on p-ERK and p-MEK, and suppresses the JAK/STAT pathway via downregulating p-JAK1, p-STAT1, p-STAT3. Furthermore, we confirmed that the combination of the mTOR inhibitor, everolimus with TNO155 is synergistic in OSCC. In summary, PTPN11 is a promising therapeutic target in OSCC that can be selectively targeted by SHP2 inhibitor such as TNO155. Our findings on the use of mTOR inhibitor, everolimus to overcome resistance to TNO155 are essential to inform on next phases of clinical trials which is warranted for the treatment of OSCC.

Advanced Human Papillomavirus–Negative Head and Neck Squamous Cell Carcinoma: Unmet Need and Emerging Therapies

Abstract Despite notable progress in the treatment of advanced head and neck squamous cell carcinoma (HNSCC), survival remains poor in patients with recurrent and/or metastatic (R/M) human papillomavirus (HPV)–negative HNSCC. Worse outcomes in patients who are HPV-negative may be partly related to loss of cell-cycle regulators and tumor suppressors as well as a noninflamed and hypoxic tumor microenvironment, both of which contribute to treatment resistance and disease progression. Anti–programmed cell death protein 1–based regimens as current standard-of-care treatment for R/M HNSCC are associated with durable responses in a limited number of patients. The anti-EGFR mAb, cetuximab, has antitumor activity in this treatment setting, but responses are short-lived and inevitably curtailed due to treatment resistance. Crosstalk between the EGFR and hepatocyte growth factor–dependent mesenchymal–epithelial transition (c-MET) receptor tyrosine kinase pathway is a known mechanism of resistance to cetuximab. Dual targeting of EGFR and c-MET pathways may overcome resistance to cetuximab in patients with HPV-negative HNSCC. Here, we review clinical data of treatments evaluated in patients with R/M HPV-negative HNSCC and highlight the potential role of combining hepatocyte growth factor/c-MET and EGFR pathway inhibitors to overcome cetuximab resistance in this population.

The Prospective role of lapatinib as an adjuvant therapy in prevalent cancers: Insights from in silico analysis targeting EGFR and HER2

IntroductionVarious pieces of evidence suggest an elevation in the levels of EGFR and HER2 in different cancers leading to the proliferation, invasion, and metastasis of cancer cells. In this study, we conducted a comprehensive investigation into the expression alterations of these two receptors in various cancers using in silico data. In addition, we investigated the therapeutic potential of lapatinib as an inhibitor of these receptors in various cancer types. MethodsRNAseq data for prevalent cancers were downloaded from The Cancer Genome Atlas (TCGA). After initial preprocessing, expression changes of HER2, EGFR, and candidate genes—identified based on their association with EGFR and HER2 signaling pathways—were examined. Human protein atlas data were utilized to assess the protein expression of HER2 and EGFR. GSE129254 was employed to identify molecular pathways and candidate genes associated with lapatinib. The protein-protein interaction network was used to identify lapatinib-influenced hub genes. Clinical data for common cancers were used to investigate the correlation between the expression of candidate genes and patients' mortality rates by Cox regression test. ResultsThe findings clearly indicated a significant increase in the expression levels of HER2 and EGFR in cancers such as kidney, lung, breast, bladder, pancreas, head and neck, stomach, and endometrial, both at the mRNA and protein levels (p-value <0.01). Additionally, more than 30 % of samples in some cancers showed a twofold increase in HER2 or EGFR expression. The analysis of GSE129254 data revealed that lapatinib reduces the expression of numerous genes associated with cell proliferation. METTL1, LYAR, LTV1, CCND1, NOP2, and DDX21 were identified as hub genes related to the effect of lapatinib. Our results demonstrated that many hub genes exhibited elevated expression in candidate cancers, and the upregulation of some of them was correlated with poor prognosis. ConclusionOur results indicate an upregulation in the expression levels of HER2 and EGFR in certain common cancers, suggesting that lapatinib, in addition to breast cancer, could be considered for the treatment of these cancers. Furthermore, we demonstrated that some genes with increased expression in prevalent cancers and associated with poor prognosis have the potential to be modulated by lapatinib.

A Novel Tryptanthrin Derivative D6 Induces Apoptosis and DNA Damage in Non-small-cell Lung Cancer Cells Through Regulating the EGFR Pathway.

Non-small-cell lung cancer is a prevalent malignancy associated with significant morbidity and mortality rates. Tryptanthrin and its derivatives have exhibited potent antitumor activity. This study aims to investigate the inhibitory effect of a novel synthesized tryptanthrin derivative D6 on proliferation and the possible mechanism of human non-small cell lung cancer cell lines (A549) in vitro. In this study, MTT assay, cell migration, colony formation assay, cell cycle analysis, cell apoptosis, JC- 1 staining assay, reactive oxygen species analysis, proteomics, western blotting, high content screening and absorption titrations analysis were performed. We found that D6 inhibited both the proliferation and migration, induced cell cycle arrest in the G2/M phase, increased levels of ROS, decreased mitochondrial membrane potential, and promoted apoptosis in A549 cells. Further mechanistic studies found that D6 reduced EGFR expression in A549 cells and inhibited the EGFR pathway by decreasing phosphorylation levels of EGFR, Stat3, AKT and Erk1/2. Moreover, DNA damage induced by D6 involved an increase in p53/MDM2 ratio and concentration-dependent accumulation of micronuclei. D6 demonstrated significant antitumor activity against A549 cells by inhibiting the EGFR signaling pathway, inducing DNA damage, and subsequently leading to oxidative stress, apoptosis, and cell cycle arrest. Our findings suggest that D6 exhibits potential as an NSCLC drug, owing to its attributes such as antiproliferative activity and ability to induce apoptosis by attenuating the EGFR-mediated signaling pathway.

Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling.

Non-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRASG12C (G12Ci) pathway inhibition remain poorly understood. Our study reveals that acute response to EGFR/RAS/RAF-pathway inhibition is spatial and culture context specific. In vivo, EGFR mutant tumor xenografts shrink by > 90% following acute EGFRi therapy, and residual tumor cells are associated with dense stroma and have increased nuclear YAP. Interestingly, in vitro EGFRi induced cell cycle arrest in NSCLC cells grown in monolayer, while 3D spheroids preferentially die upon inhibitor treatment. We find differential YAP nuclear localization and activity, driven by the distinct culture conditions, as a common resistance mechanism for selective EGFR/KRAS/BRAF pathway therapies. Forced expression of the YAPS127A mutant partially protects cells from EGFR-mediated cell death in spheroid culture. These studies identify YAP activation in monolayer culture as a non-genetic mechanism of acute EGFR/KRAS/BRAF therapy resistance, highlighting that monolayer vs spheroid cell culture systems can model distinct stages of patient cancer progression.

Lumican/Lumikine Promotes Healing of Corneal Epithelium Debridement by Upregulation of EGFR Ligand Expression via Noncanonical Smad-Independent TGFβ/TBRs Signaling.

The synthetic peptide of lumican C-terminal 13 amino acids with the cysteine replaced by an alanine, hereafter referred to as lumikine (LumC13C-A: YEALRVANEVTLN), binds to TGFβ type I receptor/activin-like kinase5 (TBR1/ALK5) in the activated TGFβ receptor complex to promote corneal epithelial wound healing. The present study aimed to identify the minimum essential amino acid epitope necessary to exert the effects of lumikine via ALK5 and to determine the role of the Y (tyrosine) residue for promoting corneal epithelium wound healing. This study also aimed to determine the signaling pathway(s) triggered by lumican-ALK5 binding. For such, adult Lum knockout (Lum-/-) mice (~8-12 weeks old) were subjected to corneal epithelium debridement using an Agerbrush®. The injured eyes were treated with 10 µL eye drops containing 0.3 µM synthetic peptides designed based on the C-terminal region of lumican for 5-6 h. To unveil the downstream signaling pathways involved, inhibitors of the Alk5 and EGFR signaling pathways were co-administered or not. Corneas isolated from the experimental mice were subjected to whole-mount staining and imaged under a ZEISS Observer to determine the distance of epithelium migration. The expression of EGFR ligands was determined following a scratch assay with HTCE (human telomerase-immortalized cornea epithelial cells) in the presence or not of lumikine. Results indicated that shorter LumC-terminal peptides containing EVTLN and substitution of Y with F in lumikine abolishes its capability to promote epithelium migration indicating that Y and EVTLN are essential but insufficient for Lum activity. Lumikine activity is blocked by inhibitors of Alk5, EGFR, and MAPK signaling pathways, while EGF activity is only suppressed by EGFR and MAPK inhibitors. qRT-PCR of scratched HTCE cells cultures treated with lumikine showed upregulated expression of several EGFR ligands including epiregulin (EREG). Treatment with anti-EREG antibodies abolished the effects of lumikine in corneal epithelium debridement healing. The observations suggest that Lum/lumikine binds Alk5 and promotes the noncanonical Smad-independent TGFβ/TBRs signaling pathways during the healing of corneal epithelium debridement.

Preparation, Evaluation, and Bioinformatics Study of Hyaluronic Acid-Modified Ginsenoside Rb1 Self-Assembled Nanoparticles for Treating Cardiovascular Diseases.

(1) Objective: To optimize the preparation process of hyaluronic acid-modified ginsenoside Rb1 self-assembled nanoparticles (HA@GRb1@CS NPs), characterize and evaluate them in vitro, and investigate the mechanism of action of HA@GRb1@CS NPs in treating cardiovascular diseases (CVDs) associated with inflammation and oxidative stress. (2) Methods: The optimal preparation process was screened through Plackett-Burman and Box-Behnken designs. Physical characterization of HA@GRb1@CS NPs was conducted using transmission electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. Stability experiments, in vitro drug release studies, and lyophilisate selection were performed to evaluate the in vitro performance of HA@GRb1@CS NPs. The anti-inflammatory and antioxidant capabilities of HA@GRb1@CS NPs were assessed using H9c2 and RAW264.7 cells. Additionally, bioinformatics tools were employed to explore the mechanism of action of HA@GRb1@CS NPs in the treatment of CVDs associated with inflammation and oxidative stress. (3) Results: The optimal preparation process for HA@GRb1@CS NPs was achieved with a CS concentration of 2 mg/mL, a TPP concentration of 2.3 mg/mL, and a CS to TPP mass concentration ratio of 1.5:1, resulting in a particle size of 126.4 nm, a zeta potential of 36.8 mV, and a PDI of 0.243. Characterization studies confirmed successful encapsulation of the drug within the carrier, indicating successful preparation of HA@GRb1@CS NPs. In vitro evaluations demonstrated that HA@GRb1@CS NPs exhibited sustained-release effects, leading to reduced MDA (Malondialdehyde) content and increased SOD (Superoxide Dismutase) content in oxidatively damaged H9c2 cells. Furthermore, it showed enhanced DPPH (2,2-Diphenyl-1-picrylhydrazyl) and ABTS+ [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] free radical scavenging rates and inhibited the release of inflammatory factors NO (Nitric Oxide) and IL-6 (Interleukin-6) from RAW264.7 cells. (4) Conclusions: The HA@GRb1@CS NPs prepared in this study exhibit favorable properties with stable quality and significant anti-inflammatory and antioxidant capabilities. The mechanisms underlying their therapeutic effects on CVDs may involve targeting STAT3, JUN, EGFR, CASP3, and other pathways regulating cell apoptosis, autophagy, anti-lipid, and arterial sclerosis signaling pathways.

Catalytically distinct IDH1 mutants tune phenotype severity in tumor models.

Mutations in isocitrate dehydrogenase 1 (IDH1) impart a neomorphic reaction that produces D-2-hydroxyglutarate (D2HG), which can inhibit DNA demethylases to drive tumorigenesis. Mutations affect residue R132 and display distinct catalytic profiles for D2HG production. We show that catalytic efficiency of D2HG production is greater in IDH1 R132Q than R132H mutants, and expression of R132Q in cellular and xenograft models leads to higher D2HG concentrations in cells, tumors, and sera compared to R132H. Though expression of IDH1 R132Q leads to hypermethylation in DNA damage pathways, DNA hypomethylation is more notable when compared to R132H expression. Transcriptome analysis shows increased expression of many pro-tumor pathways upon expression of IDH1 R132Q versus R132H, including transcripts of EGFR and PI3K signaling pathways. Thus, IDH1 mutants appear to modulate D2HG levels via altered catalysis, resulting in distinct epigenetic and transcriptomic consequences where higher D2HG levels appear to be associated with more aggressive tumors.

Lung Microbial and Host Genomic Signatures as Predictors of Prognosis in Early-Stage Adenocarcinoma.

Risk of early-stage lung adenocarcinoma recurrence after surgical resection is significant, and the postrecurrence median survival is approximately 2 years. Currently, there are no commercially available biomarkers that predict recurrence. In this study, we investigated whether microbial and host genomic signatures in the lung can predict recurrence. In 91 patients with early-stage (stage IA/IB) lung adenocarcinoma with extensive follow-up, we used 16s rRNA gene sequencing and host RNA sequencing to map the microbial and host transcriptomic landscape in tumor and adjacent unaffected lung samples. Of 91 subjects, 23 had tumor recurrence over 5-year period. In tumor samples, lung adenocarcinoma recurrence was associated with enrichment in Dialister and Prevotella, whereas in unaffected lung samples, recurrence was associated with enrichment in Sphingomonas and Alloiococcus. The strengths of the associations between microbial and host genomic signatures with lung adenocarcinoma recurrence were greater in adjacent unaffected lung samples than in the primary tumor. Among microbial-host features in the unaffected lung samples associated with recurrence, enrichment in Stenotrophomonas geniculata and Chryseobacterium was positively correlated with upregulation of IL2, IL3, IL17, EGFR, and HIF1 signaling pathways among the host transcriptome. In tumor samples, enrichment in Veillonellaceae (Dialister), Ruminococcaceae, Haemophilus influenzae, and Neisseria was positively correlated with upregulation of IL1, IL6, IL17, IFN, and tryptophan metabolism pathways. Overall, modeling suggested that a combined microbial/transcriptome approach using unaffected lung samples had the best biomarker performance (AUC = 0.83). This study suggests that lung adenocarcinoma recurrence is associated with distinct pathophysiologic mechanisms of microbial-host interactions in the unaffected lung rather than those present in the resected tumor.

A Network Pharmacological Study on the Treatment of Diminished Ovarian Reserve with Nourishing Yin Formula

Objective To identify the principal constituents of Nourishing Yin Formula, analyze its active substances and effective targets for treating DOR, and explore its potential mechanism of action. Methods The primary active constituents of Nourishing Yin Formula and their putative targets for treating DOR were identified through a search of Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (BATMAN-TCM), GeneCards, OMIM, and Uniprot databases. A protein-protein interaction network was constructed using the String database to identify shared targets between the drug and disease. These drug-disease shared targets were then subjected to GO analysis and KEGG pathway enrichment analysis using the DAVID database. Results After screening, the primary chemical constituents of Nourishing Yin Formula for treating DOR were identified, including progesterone, beta-sitosterol, 17-Beta-Estradiol, quercetin, kaempferol, etc Among the 52 critical targets for Nourishing Yin Formula in DOR treatment, the core targets were AKT1, INS, IL6, TNF, EGFR, ESR1, MYC, CTNNB1, NOS3, ERBB2, EDN1, and ESR2. Conclusions The potential mechanism of Nourishing Yin Formula in the treatment of DOR may involve the herbal compound's impact on AKT1, INS, IL6, TNF, and EGFR pathways. It regulates ovarian granulosa cell proliferation and apoptosis, and restores ovarian blood supply.

Bioinformatics analysis based on extracted ingredients combined with network pharmacology, molecular docking and molecular dynamics simulation to explore the mechanism of Jinbei oral liquid in the therapy of idiopathic pulmonary fibrosis

ObjectiveJinbei oral liquid (JBOL), which is derived from a traditional hospital preparation, is frequently utilized to treat idiopathic pulmonary fibrosis (IPF) and has shown efficacy in clinical therapy. However, there are now several obstacles facing the mechanism inquiry, including target proteins, active components, and the binding affinity between crucial compounds and target proteins. To gain additional insight into the mechanisms underlying JBOL in anti-IPF, this study used bioinformation technologies, including network pharmacology, molecular docking, and molecular dynamic simulation, with a substantial amount of data based on realistic constituents. MethodsUsing network pharmacology, we loaded 118 realistic compounds into the SwissTargetPrediction and SwissADME databases and screened the active compounds and target proteins. IPF-related targets were collected from the OMIM, DisGeNET, and GeneCards databases, and the network of IPF-active constituents was built with Cytoscape 3.10.1. The GO and KEGG pathway enrichment analyses were carried out using Metascape, and the protein-protein interaction (PPI) network was constructed to screen the key targets with the STRING database. Finally, the reciprocal affinity between the active molecules and the crucial targets was assessed through the use of molecular docking and molecular dynamics simulation. ResultsA total of 122 targets and 34 tested active compounds were summarized in this investigation. Among these, kaempferol, apigenin, baicalein were present in high degree. PPI networks topological analysis identified eight key target proteins. AGE-RAGE, EGFR, and PI3K-Akt signaling pathways were found to be regulated during the phases of cell senescence, inflammatory response, autophagy, and immunological response in anti-IPF of JBOL. It was verified by molecular docking and molecular dynamics simulation that the combining way and binding energy between active ingredients and selected targets. ConclusionsThis work forecasts the prospective core ingredients, targets, and signal pathways of JBOL in anti-IPF, which has confirmed the multiple targets and pathways of JBOL in anti-IPF and provided the first comprehensive assessment with bioinformatic approaches. With empirical backing and an innovative approach to the molecular mechanism, JBOL is being considered as a potential new medication.

S100A12 inhibits Streptococcus pneumoniae and aids in wound healing of corneal epithelial cells both in vitro and in vivo

Streptococcus pneumoniae, a leading cause of corneal infections worldwide, are extremely aggressive despite antibiotic sensitivity and exhibit increased resistance towards antibiotics. Antimicrobial peptides are often considered as potent alternatives against antibiotic resistance and here we have investigated the possible roles of S100A12, a host defense peptide, in wound healing and S. pneumoniae infection. S100A12 significantly inhibited growth of S. pneumoniae by disruption of membrane integrity along with increased generation of reactive oxygen species. Additionally, S100A12 accelerated cell migration and wound closure in human corneal epithelial cells and in a murine corneal wound model by activation of EGFR and MAPK signaling pathways.

588P Genomic landscape of acquired resistance to first-line (1L) anti-EGFR treatment in metastatic colorectal cancer (mCRC) beyond the classical EGFR pathway: Findings from the PLATFORM-B study

588P Genomic landscape of acquired resistance to first-line (1L) anti-EGFR treatment in metastatic colorectal cancer (mCRC) beyond the classical EGFR pathway: Findings from the PLATFORM-B study

Prognostic genome and transcriptome signatures in colorectal cancers

Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFβ pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.

Molecular aspects of BRAF and HER2 in prognosis of periampullary carcinoma

BackgroundBiological behaviour of Periampullary cancers (PACS) differs from pancreatic head cancer, and analysis of molecular alteration is needed. BRAF and HER2 are keys members of the RAS/RAF and EGFR pathway, playing roles in prognostic markers and therapeutic targets. MethodsA study on 89 PACS patients, undergoing Whipple Pancreaticoduodenectomy, PCR-RFLP, and qPCR methods used for SNP and mRNA expression studies. Clinicopathological and survival data collected. Molecular changes were correlated with Clinicopathological parameters. Survival outcomes were assessed by Kaplan Meir Log rank test. ResultsThe study revealed that homozygous mutant BRAF V600E was significantly higher in PAC compared to a healthy control (p = 0.0012). Whereas the genotype frequency of HER2 I1655V was similar among PAC and healthy control. The A > G change in HER2 was associated with tumor arising from duodenum (p = 0.004) and showed poor survival outcome (p = 0.001). Upregulation of BRAF and HER2 was found in 43 % of patients with synergistic effect, the median overall survival (OS) being 50.5 ± 13 months. The increased expression of HER2 was higher in early stage (p = 0.04) PAC. The gene expression did not impact the OS, whereas female gender, G3 tumors, T3-T4 depth of tumour, advanced stage, LN metastasis, LVI and PNI were poor predictors of OS. ConclusionsBRAF V600E SNP was associated with disease susceptibility, and had increased mRNA expression while HER2 I1655V SNP was associated with poor survival outcome in PAC. The increased expression of BRAF and HER2 in early tumors and their co-expression in PAC exhibit cross talk between RAS/RAF and EGFR pathway in PAC.