Epidermal Growth Factor Receptor Research Articles

Nodal Burden and Oncologic Outcomes in Patients With Residual Isolated Tumor Cells After Neoadjuvant Chemotherapy (ypN0i+): The OPBC-05/ICARO Study

PURPOSE The nodal burden of patients with residual isolated tumor cells (ITCs) in the sentinel lymph nodes (SLNs) after neoadjuvant chemotherapy (NAC) (ypN0i+) is unknown, and axillary management is not standardized. We investigated rates of additional positive lymph nodes (LNs) at axillary lymph node dissection (ALND) and oncologic outcomes in patients with ypN0i+ treated with and without ALND. METHODS The Oncoplastic Breast Consortium-05/ICARO cohort study (ClinicalTrials.gov identifier: NCT06464341 ) retrospectively analyzed data from patients with stage I to III breast cancer with ITCs in SLNs after NAC from 62 centers in 18 countries. The primary end point was the 3-year rate of any axillary recurrence. The rate of any invasive recurrence was the secondary end point. RESULTS In total, 583 patients were included, of whom 182 (31%) had completion ALND and 401 (69%) did not. The median age was 48 years. Most patients (74%) were clinically node-positive at diagnosis and 41% had hormone receptor–positive/human epidermal growth factor receptor 2–negative tumors. The mean number of SLNs with ITCs was 1.2. Patients treated with ALND were more likely to present with cN2/3 disease (17% v 7%, P < .001), have ITCs detected on frozen section (62% v 8%, P < .001), have lymphovascular invasion (38% v 24%, P < .001), and receive adjuvant chest wall (89% v 78%, P = .024) and nodal radiation (82% v 75%, P = .038). Additional positive nodes were found at ALND in 30% of patients, but only 5% had macrometastases. The 3-year rates of any axillary and any invasive recurrence were 2% (95% CI, 0.95 to 3.6) and 11% (95% CI, 8 to 14), respectively, with no statistical difference by type of axillary surgery. CONCLUSION The nodal burden in patients with ypN0(i+) was low, and axillary recurrence after ALND omission was rare in patients selected for this approach. These results do not support routine ALND in all patients with ypN0(i+).

GHRH and the prostate.

In the late 1960s and early 1970s, hypothalamic regulatory hormones were isolated, characterized and sequenced. Later, it was demonstrated hypothalamic and ectopic production of growth hormone-releasing hormone (GHRH) in normal and tumor tissues, of both humans and animals. Pituitary-type GHRH receptors (pGHRH-R) had been demonstrated to be expressed predominantly in the anterior pituitary gland but also found in other somatic cells, and significantly present in various human cancers; in addition, the expression of splice variants (SVs) of GHRH receptor (GHRH-R) has been found not only in the pituitary but in extrapituitary tissues, including human neoplasms. In relation to the prostate, besides the pGHRH-R, it has been detected the presence of truncated splice variants of GHRH-R (SV1-SV4) in normal human prostate and human prostate cancer (PCa) specimens; lastly, a novel SV of GHRH-R has been detected in human PCa. Signaling pathways activated by GHRH include AC/cAMP/PKA, Ras/Raf/ERK, PI3K/Akt/mTOR and JAK2/STAT3, which are involved in processes such as cell survival, proliferation and cytokine secretion. The neuropeptide GHRH can also transactivate the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER)-2. Thus, GHRH-Rs have become drug targets for several types of clinical conditions, including prostate-related conditions such as prostatitis, benign hyperplasia and cancer. Over the last fifty years, the development of GHRH-R receptor antagonists has been unstoppable, improving their potency, stability and affinity for the receptor. The last series of GHRH-R antagonists, AVR, exhibits superior anticancer and anti-inflammatory activities in both in vivo and in vitro assays.

Design and Synthesis of Dual Galectin-3 and EGFR Inhibitors Against Liver Fibrosis.

Liver fibrosis, mainly arising from chronic viral or metabolic liver diseases, is a significant global health concern. There is currently only one FDA-approved drug (Resmetirom) in the market to combat liver fibrosis. Both galectin-3 and epidermal growth factor receptor (EGFR) play important roles in liver fibrosis, while galectin-3 may interact with EGFR. Galectin-3 inhibitors, typically lactose or galactose derivatives may inhibit liver fibrosis. We hypothesized that targeting both galectin-3 and EGFR may have better effect against liver fibrosis. Here, EGFR inhibitor erlotinib was used in a series of designed galectin-3 inhibitors after hybridization with the pharmacophore structure in reported galectin-3 inhibitors to impede hepatic stellate cells (HSCs) activation by a typical method of click chemistry. Bioactivity test results showed that compound 29 suppressed TGF-β-induced upregulation of fibrotic markers (α-SMA, fibronectin-1, and collagen I). The preferred compound 29 displayed better binding to galectin-3 (KD = 52.29 μM) and EGFR protein (KD = 3.31 μM) by SPR assay. Further docking studies were performed to clarify the possible binding mode of compound 29 with galectin-3 and EGFR. Taken together, these results suggested that compound 29 could be a potential dual galectin-3 and EGFR inhibitor as leading compound for anti-liver fibrosis new drug development.

Liquid-Liquid Phase Separation in the Prognosis of Lung Adenocarcinoma: An Integrated Analysis.

Lung adenocarcinoma (LUAD) is a highly lethal malignancy. Liquid-Liquid Phase Separation (LLPS) plays a crucial role in targeted therapies for lung cancer and in the progression of lung squamous cell carcinoma. However, the role of LLPS in the progression and prognosis of LUAD remains insufficiently explored. This study employed a multi-step approach to identify LLPS prognosis-related genes in LUAD. First, differential analysis, univariate Cox regression analysis, Random Survival For-est (RSF) method, and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regres-sion analysis were utilized to identify five LLPS prognosis-related genes. Subsequently, LASSO Cox regression was performed to establish a prognostic score termed the LLPS-related progno-sis score (LPRS). Comprehensive analyses were then conducted based on the LPRS, including survival analysis, clinical feature analysis, functional enrichment analysis, and tumor microenvi-ronment assessment. The LPRS was integrated with additional clinicopathological factors to de-velop a prognostic nomogram for LUAD patients. Immunohistochemical validation was per-formed on clinical tissue samples to further validate the findings. Finally, the relationship be-tween KRT6A, one of the identified genes, and epidermal growth factor receptor (EGFR) muta-tions was investigated. The LPRS was established using five LLPS-related genes: IGF2BP1, KRT6A, LDHA, PKP2, and PLK1. Higher LPRS was closely associated with poor survival outcomes, gender, progression-free survival (PFS), and advanced TNM stage. Furthermore, LPRS emerged as an independent prognostic factor for LUAD. A nomogram integrating LPRS, TNM stage, and age demonstrated remarkable predictive accuracy for prognosis among patients with LUAD. LLPS likely influences LUAD prognosis through the activity of IGF2BP1, KRT6A, LDHA, PKP2, and PLK1. KRT6A exhibits significant upregulation in LUAD, particularly in patients with EGFR mutations. This study introduces a novel LPRS model that demonstrates high accuracy in pre-dicting the clinical prognosis of LUAD. Moreover, the findings suggest that KRT6A may play a critical role in the LLPS-mediated malignant progression of LUAD.

Yigu decoction regulates plasma miRNA in postmenopausal osteoporosis patients: a randomized controlled trial

BackgroundPostmenopausal osteoporosis (PMOP) is a serious condition that affects elderly individuals. Our previous study revealed that Yigu decoction (YGD) effectively improved bone mineral density (BMD) in elderly individuals, but the mechanism underlying this effect remains unclear. In this study, we investigated the relationships among YGD, microRNAs (miRNAs), and bone metabolism by assessing the effects of YGD on the miRNA levels in patient plasma to provide a scientific basis for treating PMOP with YGD.MethodsIn this clinical trial, 60 patients were randomly assigned to the YGD group or the control group (ratio of 1:1) and treated for 3 months. The primary outcome measure was BMD, and the secondary outcome measures included plasma miRNA levels, visual analogue scale (VAS) scores, alkaline phosphatase (ALP) levels, anti-tartrate acid phosphatase (TRACP-5b) levels and traditional Chinese medicine (TCM) syndrome scores. We assessed the regulatory roles of miRNAs in PMOP patients by analysing publicly available data from the Gene Expression Omnibus (GEO) database. Bioinformatics methods were also used to explore the mechanism by which YGD regulates miRNAs that are involved in bone metabolism.ResultsCompared with those before treatment, the BMD, ALP levels, TRACP-5b levels, TCM syndrome scores and VAS scores improved in both groups after 3 months of treatment (P < 0.05). A total of 82 miRNAs differed between the groups. After analysing data from the GEO database, we confirmed that miR-133a-3p is the key molecule that mediates the effects of YGD intervention on PMOP. GO analysis of key genes suggested that gene enrichment was more pronounced in response to hormones, cellular response to growth factor stimulation, and positive regulation of physiological and metabolic processes. KEGG analysis revealed that these genes were enriched mainly in the PI3K-Akt, FOXO, and JAK-STAT pathways and other pathways. The results of the protein‒protein interaction (PPI) network analysis revealed that epidermal growth factor receptor (EGFR), Insulin-like growth factor 1 (IGF-1), Caveolin-1 (Cav-1) and others were core proteins.ConclusionThis study demonstrated that YGD is beneficial in the treatment of PMOP, ameliorating clinical symptoms and bone turnover indices. Moreover, the inhibition of miR-133a-3p expression may be the key mechanisms by which YGD regulates bone metabolism in the treatment of PMOP, although YGD regulates bone metabolism in a multitarget and multipathway manner.

Efficacy of disitamab vedotin in non-small cell lung cancer with HER2 alterations: a multicenter, retrospective real-world study

BackgroundNon-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) alterations poses a substantial treatment challenge. Current HER2-targeted therapies offer limited efficacy. Antibody-drug conjugates (ADCs) targeting HER2 have emerged as a promising therapeutic strategy. This study aimed to evaluate the clinical response to a novel ADC drug Disitamab vedotin (RC48) in advanced NSCLC with HER2 alterations.MethodsThis study conducted a retrospective review of patients harboring HER2 alterations treated with RC48 in the real world. Clinical outcomes were evaluated in terms of objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS).ResultsOut of 22 patients, 21 (95.5%) received RC48 combination therapy, while one received RC48 monotherapy. The ORR of all patients reached 45.5%, and the DCR stood at 90.9%. The median PFS (mPFS) was 7.5 months. Among patients receiving RC48 combination therapy, the ORR was 47.7%, and the mPFS of 8.1 months. The combination of RC48 with platinum+/- bevacizumab resulted in the highest ORR of 71.4% (5 out of 7 patients), with HER2 TKI following at a 50.0% ORR (4 out of 8 patients). First-line (1L) treatment with RC48 showed an ORR of 62.5% (5 out of 8 patients), second-line (2L) treatments had a 57.1% ORR (4 out of 7 patients), and beyond second-line (>2L) treatments exhibited a 14.3% ORR (1 out of 7 patients). Patients with 1L, 2L, or >2L treatment had a mPFS of 8.1 months, 7.2 months, and 7.4 months, respectively. Patients with HER2 mutations or amplifications, and those with concurrent mutations and amplifications at baseline, showed mPFS of 8.1 months, 9.4 months, and 7.4 months, respectively. The mPFS was significantly longer in patients with HER2 amplification. The most common adverse events included hand-foot syndrome (54.5%), asthenia (50.0%), decreased white blood cell count (45.5%), and liver impairment (45.5%). Grade 3 adverse events occurred in one (4.5%) patient.ConclusionRC48, particularly in combination regimens, demonstrates promising efficacy in advanced NSCLC with HER2 alterations. These findings underscore the need for further research to validate RC48’s application in clinical practice.

Inetetamab for injection in combination with vinorelbine weekly or every three weeks in HER2-positive metastatic breast cancer: A multicenter, randomized, phase II clinical trial

Abstract Objective We aimed to investigate the pharmacokinetics, safety, efficacy, and immunogenicity of different dosing regimens (weekly and every three weeks) of inetetamab in combination with vinorelbine in human epidermal growth factor receptor 2 (HER2)+ patients with metastatic breast cancer who had received one or more chemotherapy regimens. Methods HER2+ patients with metastatic breast cancer who had received one or more chemotherapy regimens were included. Eligible patients received inetetamab administered weekly or every three weeks in combination with vinorelbine injection chemotherapy. Pharmacokinetics, safety, efficacy, and immunogenicity were compared between the groups. Results Sixty HER2+ patients were randomized into a single-week administration group ( n = 29) and a three-week administration group ( n = 31). After the final dose in the single-week administration group and the three-week administration group, the mean Cmax values were 79.773 μg/mL and 146.083 μg/mL; the mean Cmin values were 30.227 μg/mL and 11.926 μg/mL; the mean AUCtau values were 7328.443 μg·h/mL and 22647.101 μg·h/mL; and the mean Cav values were 43.622 μg/ mL and 44.935 μg/mL, respectively. The best overall response (BOR) rates at 24 weeks and unconfirmed BOR rates at 24 weeks were both 40.7% in the single-week dosing group and 40.7% in the three-week dosing group, and the 24-week confirmed disease control rates (DCRs) were 88.9% and 81.5%, respectively. The incidence of adverse events (AEs) was generally consistent across all levels. Conclusion There were slight differences in the mean Cmax, Cmin, AUCtau and Cav between the three-week dosing group and the single-week dosing group, and the mean steady-state concentrations of Cav were comparable; however, there were no differences in efficacy, safety or immunogenicity between the two groups.

Extracellular proximal interaction profiling by cell surface-targeted TurboID reveals LDLR as a partner of liganded EGFR.

Plasma membrane proteins play pivotal roles in receiving and transducing signals from other cells and from the environment and are vital for cellular functionality. Enzyme-based, proximity-dependent approaches, such as biotin identification (BioID), combined with mass spectrometry have begun to illuminate the landscape of proximal protein interactions within intracellular compartments. To extend the potential of these approaches to study the extracellular environment, we developed extracellular TurboID (ecTurboID), a method designed to profile the interactions between proteins on the surfaces of living cells over short timescales using the fast-acting biotin ligase TurboID. After optimizing our experimental and data analysis strategies to capture extracellular proximity interactions, we used ecTurboID to reveal the proximal interactomes of several plasma membrane proteins, including the epidermal growth factor receptor (EGFR). We found that EGF stimulation induced an association between EGFR and the low-density lipoprotein receptor (LDLR) and changed the interactome of LDLR by increasing its proximity with proteins that regulate EGFR signaling. The identification of this interaction between two well-studied and clinically relevant receptors illustrates the utility of our modified proximity labeling methodology for identifying dynamic extracellular associations between plasma membrane proteins.

Mechanism of Asperosaponin VI Related to EGFR/MMP9/AKT/PI3K Pathway in Treatment of Rheumtoid Arthritis.

To explore the mechanism of action of asperosaponin VI (AVI) in the treatment of rheumatoid arthritis (RA) and validate it in ex vivo experiments using network pharmacology and molecular docking methods. The predicted targets of AVI were obtained from PharmMaper, UniProt and SwissTarget Prediction platforms, the disease targets were collected from Online Mendelian Inheritance in Man, Therapeutic Target Database and GeneCards databases, the intersection targets of AVI and RA were obtained from Venny 2.1.0, and the protein-protein interaction (PPI) network was obtained from STRING database, which was analyzed by Cytoscape software and screened to obtain the core targets. Cytoscape software was used to analyze PPI network and screen the core targets. Based on the Database for Annotation, Visualization and Integrated Discovery database, Gene Ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed, and Cytoscape software was used to construct the "Disease-Pathway-Target-Drug" network, which was finally verified by molecular docking and animal experiments. Network pharmacological studies showed that AVI was able to modulate 289 targets, with 102 targets for the potential treatment of RA, with the core pathway being the AKT/PI3K signaling pathway, and the core targets being the epidermal growth factor receptor (EGFR) and matrix metalloproteinase 9 (MMP9). Molecular docking results showed that AVI could produce strong binding with both of the 2 core targets. In vitro cellular experiments showed that AVI reduced nitric oxide, prostaglandin E2, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1 β levels (P<0.05) and inhibited cyclooxygenase-2, nitric oxide synthase, EGFR, MMP9, phosphorylated phosphoinositide 3-kinase (p-PI3K), and phosphorylated serine-threonine kinase (p-AKT) proteins (P<0.05). The results of in vivo studies showed that AVI improved RA score and foot swelling thickness and decreased TNF-α, IL-6, p-PI3K and p-AKT levels in RA rats (P<0.05). AVI exerts anti-inflammatory and anti-RA effects which might be related to the EGFR/MMP9/AKT/PI3K pathway.

Crystal Structures and Biological Profiles of Novel Tridentate Schiff Bases Nickel (II) Complexes

ABSTRACTNovel bioactive ternary nickel (II) complexes, [Ni(5BrSal‐Phe)(phen)] (1) and [Ni(5BrSal‐Tyr)(phen)] (2) (5BrSal‐Tyr: Schiff base derived from 5‐bromosalicylaldehyde and L‐tyrosine, 5BrSal‐Phe: Schiff base derived from 5‐bromosalicylaldehyde and L‐phenylalanine, phen: 1,10‐phenanthroline), have been synthesized and characterized by electronic absorption spectroscopy, CHN, FTIR, ESI‐MS and X‐ray crystallography techniques. Interaction of the complexes with biomolecules (calf thymus DNA (CT‐DNA) and bovine serum albumin (BSA)) has been investigated by electronic absorption and fluorescence spectroscopy. The results show that the complexes can bind to CT‐DNA via a minor groove binding mode. Moreover, the fluorescence quenching mechanism between the complexes and BSA is a static quenching process. The antiproliferative activities of the complexes against breast cancer cells (MCF‐7 and MDA‐MB‐231) and healthy breast epithelial cells (MCF‐10A) were investigated. The complex 2 was found to have promising antiproliferative activity in selected cell line, with lower IC50 values than cisplatin. Molecular docking studies suggest that the complexes may serve as potential chemotherapeutic agents. These complexes have been observed to interact with various targets within cells, including the epidermal growth factor receptor (EGFR), bovine serum albumin (BSA), and B‐DNA. Analyses indicate that these interactions are supported not only by conventional hydrogen bonds but also van der Waals forces and π‐π interactions. Additionally, determining binding constants and regions enhances our understanding of how the complexes interact with target molecules. The results emphasize the importance of the complexes in cancer therapy by highlighting the necessity of understanding their molecular‐level interactions with targets.

Ultrasound‐Responsive Lipid Nanoparticles for Targeted Therapy and Controlled Drug Release in Non‐Small Cell Lung Cancer

AbstractMultifunctional drug delivery systems offer tremendous potential for improving antitumor efficacy, precise drug targeting, and controlled drug release in treating non‐small cell lung cancer (NSCLC). In this study, the study develops a novel tumor‐targeting ultrasound‐responsive lipid nanoparticle (TUSL) platform capable of responding to external stimulation, enabling precise drug delivery with controlled release at the tumor site while minimizing systemic exposure and side effects. The TUSL platform is designed to carry doxorubicin (DOX) and tetrandrine (TET), specifically for drug‐resistant NSCLC. The developed TUSL exhibits a nano sized spherical structure with a hydrodynamic size of 141.8 nm, accommodating anti‐cancer drugs with loading capacities of 3.8% and 6.2% for TET and DOX, respectively. TUSL is engineered to target the epidermal growth factor receptor (EGFR) while demonstrating an ultrasound‐triggered drug release profile. Through the generation of CO2 bubbles upon ultrasound stimulation, the TUSL enhances DOX and TET internalization into tumor cells. In tumor‐bearing mice, TUSL administration demonstrates a superior tumor accumulation with minimal off‐target toxicity. The combined treatment with DOX and TET within TUSL exhibits synergistic effects, effectively inhibiting the growth of drug‐resistant NSCLC tumors. These findings highlight the efficacy of the EGFR‐targeted TUSL formulation in overcoming drug resistance and enhancing therapeutic outcomes in NSCLC.

Phage-Templated Synthesis of Targeted Photoactive 1D-Thiophene Nanoparticles.

Thiophene-based nanoparticles (TNPs) are promising therapeutic and imaging agents. Here, using an innovative phage-templated synthesis, a strategy able to bypass the current limitations of TNPs in nanomedicine applications is proposed. The phage capsid is decorated with oligothiophene derivatives, transforming the virus in a 1D-thiophene nanoparticle (1D-TNP). A precise control of the shape/size of the nanoparticles is obtained exploiting the well-defined morphology of a refactored filamentous M13 phage, engineered by phage display to selectively recognize the Epidermal Growth Factor Receptor (EGFR). The tropism of the phage is maintained also after the bioconjugation of the thiophene molecules on its capsid. Moreover, the 1D-TNP proved highly fluorescent and photoactive, generating reactive oxygen species through both type I and type II mechanisms. The phototheranostic properties of this platform are investigated on biosystems presenting increasing complexity levels, from in vitro cancer cells in 2D and 3D architectures, to the in vivo tissue-like model organism Hydra vulgaris. The phage-templated 1D-TNP showed photocytotoxicity at picomolar concentrations, and the ability to deeply penetrate 3D spheroids and Hydra tissues. Collectively the results indicate that phage-templated synthesis of organic nanoparticles represents a general strategy, exploitable in many diagnostic and therapeutic fields based on targeted imaging and light mediated cell ablation.

Camel milk-derived exosomes as novel nanocarriers for curcumin delivery in lung cancer

Cancer remains a leading cause of mortality, with non-small cell lung cancer (NSCLC) being a primary contributor to cancer-related deaths. Traditional treatment strategies such as chemotherapy, radiation, and hormone therapy often present challenges, including severe side effects, drug resistance, and toxicity. Recent advancements in nanotechnology aim to enhance the effectiveness of cancer therapies by targeting drugs selectively and specifically to tumor cells. Among these innovations, exosomes, or small extracellular vesicles (EVs), have emerged as promising carriers for drug delivery due to their natural origin and ability to encapsulate both small molecules and biologics. This study explores the use of exosomes derived from camel milk in Hail, Saudi Arabia, as a vehicle for delivering curcumin (CUR), a polyphenol with known chemopreventive properties but limited bioavailability. Camel milk was processed to isolate exosomes through differential centrifugation, followed by characterization using dynamic light scattering, zeta potential measurements, and Western blot analysis to confirm exosomal markers. The encapsulation of CUR into camel milk-derived exosomes demonstrated a 20% loading efficiency as analyzed by UPLC. In vitro antiproliferative assays revealed that the exosomal formulation of CUR (ExoCUR) significantly enhanced cytotoxicity against drug -sensitive (A549) and taxol-resistant (A549TR) lung cancer cells compared to free CUR. Molecular docking studies and molecular dynamics simulations indicated that CUR has a strong binding affinity for the epidermal growth factor receptor (EGFR), comparable to the established drug gefitinib. Furthermore, CUR effectively downregulated EGFR and STAT3 expression in cancer cells, suggesting its potential to disrupt key signaling pathways involved in tumor progression. Our findings highlight the potential of camel milk-derived exosomes as an effective and biocompatible delivery system for CUR, offering a promising strategy to overcome the limitations of current cancer therapies and enhance the therapeutic efficacy of chemopreventive agents.

Inhibitory effect of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone against NSCLC with L858R/T790M/C797S mutant EGFR

Epidermal growth factor receptor (EGFR)-activating mutations are critical factors in the development of EGFR-driven non-small-cell lung cancer (NSCLC), and molecular targeted therapies have focused on inhibiting these mutations. EGFR tyrosine kinase inhibitors (TKIs) have remarkable inhibitory effects on NSCLC with EGFR mutations. However, acquired resistance limits the clinical application of EGFR-TKIs, highlighting the need for discovery of novel therapeutic strategies. 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone is a natural product derived from Garcinia xanthochymus, has shown potential anti-tumor activity, but the underlying mechanism needs further elucidation. In this study, we developed Ba/F3 and NIH/3T3 cells harboring EGFR L858R/T790M/C797S mutation, and then found that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exerted inhibitory effects against cells with EGFR L858R/T790M/C797S mutation. Additionally, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone exhibited potent anti-tumor activity against cells harboring the triple-mutant EGFR by promoting apoptosis and inducing changes in cell cycle distribution. Furthermore, 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone was found to significantly reduce tumor growth via suppressing the phosphorylation of EGFR in tumor tissues. These effects are associated with binding of 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone to EGFR resulting in the suppression of extracellular signal-regulated kinase (Erk) phosphorylation. In conclusion, our results suggest that 1,4,5,6-tetrahydroxy-7,8-diprenylxanthone may be a potential novel candidate for further investigation and treatment of NSCLC with the triple-mutant EGFR.

L858R/L718Q and L858R/L792H Mutations of EGFR Inducing Resistance Against Osimertinib by Forming Additional Hydrogen Bonds.

Acquired resistance to first-line treatments in various cancers both promotes cancer recurrence as well as limits effective treatment. This is true for epidermal growth factor receptor (EGFR) mutations, for which secondary EGFR mutations are one of the principal mechanisms conferring resistance to the covalent inhibitor osimertinib. Thus, it is very important to develop a deeper understanding of the secondary mutational resistance mechanisms associated with EGFR mutations arising in tumors treated with osimertinib to expedite the development of innovative therapeutic drugs to overcome acquired resistance. This work uses all-atom molecular dynamics (MD) simulations to investigate the conformational variation of two reported EGFR mutants (L858R/L718Q and L858R/L792H) that resist osimertinib. The wild-type EGFR kinase domain and the L858R mutant are used as the reference. Our MD simulation results revealed that both the L718Q and L792H secondary mutations induce additional hydrogen bonds between the residues in the active pocket and the residues with the water molecules. These additional hydrogen bonds reduce the exposure area of C797, the covalent binding target of osimertinib. The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue-residue and residue-solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery.

ERO1A levels are a prognostic indicator in EGFR mutated non small cell lung cancer

We have identified endoplasmic reticulum oxidoreductase 1 alpha (ERO1A) as a poor prognostic indicator in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (EGFRMUT-NSCLC). In addition, comparison of high versus low ERO1A expression among cohorts of EGFRMUT-NSCLC primary samples revealed that ERO1A expression correlated with increased expression of proteins that regulate secretion. Using the CPTAC proteomic data set in lung adenocarcinoma we found that high ERO1A protein expression correlated with both extracellular matrix and matrix modifying enzymes. In this report, we found that ablating ERO1A expression was a determinant of clonogenicity, tumor sphere formation, spheroid growth and growth in vivo, as well as response to Osimertinib. We validated that ERO1A-knockout EGFRMUT-LUAD cell lines demonstrated a reduction in secretion of both laminin gamma 2 (LAMC2) and the collagen modifying enzyme lysyl oxidase-like 2 (LOXL2). Our work supports the role of ERO1A in modulating the tumor microenvironment that is likely to contribute to tumor progression.

Current status and challenges in HER2 IHC assessment: scoring survey results in Japan.

This study aimed to assess the concordance of human epidermal growth factor receptor 2 (HER2) expression scoring by immunohistochemistry (IHC) among practicing pathologists in Japan, given the challenging nature of scoring and the critical role of HER2 status in breast cancer management. Whole slide images (WSI) from 20 invasive breast cancer cases (1 representative WSI per case) selected to represent a diverse IHC scores and staining patterns were used in an online survey involving seven reference pathologists who established consensus HER2 IHC scores (0 to 3 +) decided by majority interpretation. Participating pathologists nationwide scored the same 20 WSI cases online using the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2018 guidelines. Deidentified case metadata were registered in the uPath system. A total of 144 participating pathologists responded. The scoring results of the participating pathologists most commonly agreed with the consensus IHC score, followed by a ± 1 point deviation and no survey responses with > 1 point deviation. The mean percentage of agreement with the consensus score for all 20 cases was 63.4%. In cases where the reference pathologists' scores were discordant, the participating pathologists also showed a lower concordance rate. This study highlighted the current status of HER2 expression scoring by IHC for breast cancer among pathologists in Japan. These findings underscore the challenges in HER2 IHC scoring cases and emphasize the need for improved standardization and training, especially in the evolving landscape of HER2-targeted therapies.

Cytomorphological and histomorphological features of lung adenocarcinoma with epidermal growth factor receptor mutation and anaplastic lymphoma kinase gene rearrangement

Cytomorphological and histomorphological features of lung adenocarcinoma with epidermal growth factor receptor mutation and anaplastic lymphoma kinase gene rearrangement

Case report: Efficacy of later-line fam-trastuzumab deruxtecan in a patient with triple-positive breast cancer with brain metastases

Fam-trastuzumab deruxtecan (T-DXd) has demonstrated substantial antitumor activity and durable responses in patients with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. We report here the treatment outcomes of T-DXd in a patient with HER2+ breast cancer with brain metastases that repeatedly recurred and progressed after two lines of salvage therapy. In 2016, a 23-year-old G0P0 female with risk factors including menarche at age 9 years, Li-Fraumeni syndrome, and a strong family history of cancer was diagnosed with bilateral, triple-positive breast cancer. She received chemotherapy, HER2-targeted therapies, total mastectomy, and locoregional radiotherapy, but a brain metastasis in the left parieto-occipital lobe was detected in 2020. After receiving capecitabine, lapatinib, gonadotropin-releasing hormone (GnRH) agonist, and tamoxifen, multiple new lesions appeared in the brain after 14 months. The patient then received capecitabine, neratinib, GnRH agonist, and letrozole; however, her brain metastases still progressed after 7 months. In 2022, she started T-DXd treatment. Good response to treatment was observed 4 months later, including a continuous decrease in the cancer antigen 15-3 level, a reduction in the size of the major brain tumor, and the absence of new lesions. Now aged 30, the patient is continuing to receive T-DXd treatment to prevent recurrence. We conclude that T-DXd was effective for the treatment of brain metastases in this young patient with triple-positive metastatic breast cancer who had multiple risk factors and had received several anti-HER2 therapies prior to T-DXd.

Evaluation of early cardiotoxicity in HER2-positive breast cancer patients receiving radiotherapy and concurrent trastuzumab.

Overexpression of human epidermal growth factor receptor 2 (HER-2) is associated with aggressive disease in breast cancer. Trastuzumab and radiotherapy are standard treatments for patients with HER-2 + breast cancer, but they may increase the risk of cardiotoxicity. This study aimed to assess early cardiotoxicity in patients receiving radiotherapy (RT) and concurrent trastuzumab. The study included 116 patients with HER-2 + breast cancer who received concurrent treatment with trastuzumab and RT (52 right-side; 64 left-side). Five left ventricular ejection fraction (LVEF) measurements were performed: one before treatment and four subsequent measurements taken at three-month intervals. LVEF was also assessed before (preRT-EF) and after (postRT-EF) radiotherapy. The baseline LVEF was 62.27 ± 5.5%, while the 12-month LVEF was 59.8 ± 5.8% (p < 0.05). In subgroups, post-RT LVEF values ​​were significantly lower than pre-RT LVEF values (p < 0.05). No significant difference was found between the reduction in LVEF for patients receiving 50Gy and 60Gy doses. Moreover, the contribution of regional lymph node irradiation to the decrease in LVEF could not be demonstrated. A positive correlation was found between the total trastuzumab dose and the decrease in LVEF from preRT to postRT. Additionally, a positive correlation was observed between the total taxane dose and the reduction in LVEF from baseline to 9months, both in the overall group and in the left breast cancer group. In our study,it was found that not only trastuzumab but also taxane-based agents could be cardiotoxic. However, no connection was found between RT doses and the decrease in LVEF.