Epidermal Growth Factor Receptor Research Articles

Gastric Cancer: Molecular Characterization, Therapeutic Innovations, and Perspectives

Abstract Introduction Gastric cancer is the fifth most common neoplasm and the fourth leading cause of cancer-related death in the world. The present review aims to offer to the oncologic community the molecular characterization of gastric cancer, the therapeutic innovations and the perspectives for the systemic therapy for gastric cancer. Materials and Methods We searched for articles in the PubMed database using Medical Subject Headings (MeSH). The latest publications and proceedings of meetings were also reviewed. Results The cornerstone of the systemic therapy for gastric cancer is the dual combination of fluoropyrimidines and platin-based chemotherapy. Nevertheless, it is recommended that gastric cancer patients are tested for human epidermal growth factor receptor 2 (HER2), high-frequency microsatellite instability (MSI-H), programmed cell death-ligand 1(PD-L1), and claudin 18.2 expression. If HER2-positive, trastuzumab plus pembrolizumab should be added to the doublet chemotherapy. Anti-programmed cell death-1 (anti-PD-1) therapy, such as nivolumab or pembrolizumab, should also be added to chemotherapy in MSI-H and in the PD-L1-positive patients. Patients who present overexpression of claudin 18.2 should be treated with the combination of zolbetuximab and oxaliplatin-based chemotherapy. Immunotherapy may also be considered in patients with high tumor mutational burden. Clinical trials evaluating fibroblast growth factor receptor 2 (FGFR2) inhibitors and the dual inhibition anti-PD-1 and anti-T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (anti-TIGIT) are promising. Conclusions The clinical applicability of precision medicine in gastric cancer has risen in the past few decades, leading to substantial improvements in the efficacy of the systemic therapy. Testing patients for biomarkers is paramount for the appropriate management of advanced disease. Ongoing clinical trials evaluating new therapeutic strategies are promising and offer optimism for the patients affected by this challenging disease.

Osimertinib for Epidermal Growth Factor Receptor Exon 20 Insertion and Exon 21Osimertinib for Epidermal Growth Factor Receptor Exon 20 Insertion and Exon 21 L858R Mutations in Lung Adenocarcinoma L858R Mutations in Lung Adenocarcinoma

Patients with lung adenocarcinoma harbouring epidermal growth factor receptor (EGFR) mutations are usually treated with tyrosine kinase inhibitors (TKIs). However, patients with lung adenocarcinoma harbouring EGFR exon 20 insertion mutations are generally resistant to TKIs. Herein, we report the case of a woman who presented with right shoulder pain for 6 months after undergoing left lower lobectomy for lung adenocarcinoma in 2017. Imaging revealed extensive disease spread, and biopsy confirmed adenocarcinoma, with EGFR exon 20 insertion and exon 21 L858R mutations. After treatment with palliative intensity-modulated radiotherapy to the right shoulder, the patient was prescribed osimertinib 80mg. However, a month into the treatment, the patient developed neutropenia. Osimertinib was discontinued and later restarted at half the initial dose. The patient subsequently showed a dramatic improvement in both haematological and oncological parameters, suggesting that reduced-dose osimertinib is effective for patients with adenocarcinoma harbouring EGFR exon 20 insertion and exon 21 L858R mutations.

Gene targets with therapeutic potential in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Major treatments include liver transplantation, resection, and chemotherapy, but the 5-year recurrence rate remains high. Late diagnosis often prevents surgical intervention, contributing to poor patient survival rates. Carcinogenesis in HCC involves genetic alterations that drive the transformation of normal cells into malignant ones. Enhancer of zeste homolog 2 (EZH2), a key regulator of cell cycle progression, is frequently upregulated in HCC and is associated with advanced stages and poor prognosis, making it a potential biomarker. Additionally, signal transducer and activator of transcription 3, which binds to EZH2, affects disease staging and outcomes. Targeting EZH2 presents a promising therapeutic strategy. On the other hand, abnormal lipid metabolism is a hallmark of HCC and impacts prognosis. Fatty acid binding protein 5 is highly expressed in HCC tissues and correlates with key oncogenes, suggesting its potential as a biomarker. Other genes such as guanine monophosphate synthase, cell division cycle associated 5, and epidermal growth factor receptor provide insights into the molecular mechanisms of HCC, offering potential as biomarkers and therapeutic targets.

A Case Report on Prolonged Response with T-DM1 in Recurrent Advanced Breast Cancer Setting

Breast cancer holds the dubious distinction of being the most prevalent malignant tumour among women worldwide. The 5-year survival rate for patients with advanced or metastatic forms of the disease is estimated at a mere 23%, with approximately 20% of cases exhibiting an amplification of the human epidermal growth factor receptor 2 (HER2). HER2 overexpression was linked to a dismal prognosis prior to the advent of targeted HER2 therapies. The introduction of ado-trastuzumab emtansine (T-DM1) has emerged as one of the standard treatment options for HER2-positive breast cancer patients who experience a recurrence or progression of the disease. This case concerns a patient with recurrent metastatic breast cancer who achieved an unusually extended period of time without the disease progressing while on T-DM1 treatment. After experiencing disease progression on multiple treatment lines involving trastuzumab, the patient achieved a nearly complete clinical remission (cCR) with T-DM1 therapy. The availability of cost-effective biosimilars has expanded access to advanced biologic therapies, which were previously limited to a small segment of the population due to the cost barrier.

Radiomics based on dual-layer spectral detector CT for predicting EGFR mutation status in non-small cell lung cancer.

To explore the value of dual-layer spectral computed tomography (DLCT)-based radiomics for predicting epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC). DLCT images and clinical information from 115 patients with NSCLC were collected retrospectively and randomly assigned to a training group (n=81) and a validation group (n=34). A radiomics model was constructed based on the DLCT radiomic features by least absolute shrinkage and selection operator (LASSO) dimensionality reduction. A clinical model based on clinical and CT features was established. A nomogram was built combining the radiomic scores (Radscores) and clinical factors. Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA) were used for the efficacy and clinical value of the models assessment. A total of six radiomic features and two clinical features were screened for modeling. The AUCs of the radiomic model, clinical model, and nomogram were 0.909, 0.797, and 0.922, respectively, in the training group and 0.874, 0.691, and 0.881, respectively, in the validation group. The AUCs of the nomogram and the radiomics model were significantly higher than that of the clinical model, but no significant difference was found between them. DCA revealed that nomogram had the greatest clinical benefit at most threshold intervals. Nomogram integrating clinical factors and pretreatment DLCT radiomic features can help evaluate the EGFR mutation status of patients with NSCLC in a noninvasive way.

Persist or resist: Immune checkpoint inhibitors in EGFR-mutated NSCLC.

Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), especially third-generation TKIs, have significantly improved the progression-free survival and overall survival of non-small cell lung cancer (NSCLC) patients with EGFR mutation, TKI resistance is inevitable for most patients. Over the past few years, immune checkpoint inhibitors (ICIs) have significantly improved the survival for EGFR-wild type NSCLC patients. However, no significantly improved benefits were observed with ICI monotherapy in EGFR-mutated patients. EGFR-mutated NSCLC shows more heterogeneity in tumor mutational burden (TMB), programmed cell death-ligand 1 (PD-L1), and immune microenvironment characteristics. Whether ICIs are suitable for EGFR-mutated NSCLC patients remains to be elucidated. In this review, we summarized clinical trials of ICIs or combined therapy in EGFR-mutated NSCLC patients. We further discussed the factors determining the efficacy of ICIs in EGFR-mutated NSCLC patients, the mutation subtypes and microenvironment characteristics of potential responders. More importantly, we provided insights into areas worth further investigation in the future.

Mammographic parameters as predictors of molecular subtype of breast cancer: a prospective analysis

BackgroundThe prevalence of breast cancer is increasing globally and its early detection is the need of hour for giving the patient a long disease-free meaningful life. The latest management regimes depend upon the biological behavior of the breast cancer that itself relies upon expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her 2) neu status for its molecular subtyping.AimTo determine the predictive value of mammographic parameters in identifying the estrogen and progesterone hormone receptor status, human epidermal growth factor receptor 2 (Her 2) neu expression and molecular subtypes of breast cancer.MethodsA prospective observational study was conducted from January 2021 to September 2022 in a tertiary care institute. The study enrolled 51 females with histopathologically proven invasive breast carcinoma. The patients underwent digital mammography followed by tissue biopsy. Mammographic parameters were based on Breast Imaging-Reporting and Data System (BI-RADS) imaging features. The molecular subtypes of breast cancer were grouped into four subtypes based on St. Gallen International Expert Consensus Panel 2013. The mammographic features were then statistically correlated with molecular subtypes of breast cancer.ResultsLuminal type A was the most common molecular subtype in our study [ 17 (33.33%)] followed by triple negative type [10(19.61%)]. Tumors with non-circumscribed margins were predicted to be Luminal A or Luminal B subtype (p value < 0.02). Tumor with microcalcification was strongly predicted to be Her 2 subtype with a statistically significant association (p value < 0.001). Circumscribed tumors with absence of microcalcification were predicted to be triple-negative type of breast cancer.ConclusionsKey features in mammography were significantly associated with breast cancer molecular subtypes. Knowledge of such correlations could help clinicians stratify breast cancer patients according to their likely molecular subtypes, potentially enabling earlier, more effective treatment or aiding in therapeutic decisions in countries where immunohistochemical (IHC) hormone receptor and Her 2 testing is not readily available.

Integration of pharmacophore-based virtual screening, molecular docking, ADMET analysis, and MD simulation for targeting EGFR: A comprehensive drug discovery study using commercial databases.

The epidermal growth factor receptor (EGFR), a crucial component of cellular signaling pathways, is frequently dysregulated in a range of cancers. EGFR targeting has become a viable approach in the development of anti-cancer medications. This study employs an integrated approach to drug discovery, combining multiple computational methodologies to identify potential EGFR inhibitors. The co-crystal ligand for the EGFR protein (R85) (PDB ID: 7AEI) was employed as a model for developing pharmacophore hypotheses. Nine databases underwent a ligand-based virtual screening, and 1271 hits meeting the screening criteria were chosen. EGFR protein crystal structure was obtained from the PDB database (PDB ID: 7AEI) and prepared. The hit compounds identified during virtual screening were docked to the prepared EGFR receptor to predict binding affinities by using the glide tool's standard precision mode. The top ten compounds were chosen, and their affinities of binding ranged from -7.691 to -7.338 kcal/mol. The ADMET properties of the selected compounds were predicted, and three compounds MCULE-6473175764, CSC048452634, and CSC070083626 showed better QPPCaco values compared to other identified compounds, so these were selected for further stability analysis. To confirm the stability of the protein-ligand complexes, a 200 ns molecular dynamics (MD) simulation was run using the binding sites of the top three compounds against the EGFR receptor. These results suggest that the selected compounds may be lead compounds in suppressing the biological activity of EGFR, additional experimental investigation is required.

Suppression of Epidermal Growth Factor Receptor by Erlotinib Attenuates Carvacrol-induced Skin Inflammation.

Epidermal growth factor receptors (EGFRs) regulate the growth and repair process of epithelia, as well as carcinogenesis. Activation of TRPV3 by carvacrol stimulates skin inflammation and epidermal hyperplasia; the latter can be suppressed by EGFR inhibition. However, whether EGFR signalling is responsible for skin inflammation remains elusive. The current study investigated the effect of erlotinib, an EGFR inhibitor, on skin inflammation in a carvacrol-induced atopic dermatitis mouse model. It was observed that erlotinib significantly attenuated carvacrol-induced overexpression of proinflammatory cytokines and suppressed peripheral blood mononuclear cell recruitment in HaCaT keratinocytes. In addition, it was demonstrated that erlotinib suppressed carvacrol-induced Akt and NF-κB signalling pathways. Furthermore, inhibition of Akt and NF-κB signalling pathways also attenuated the carvacrol-induced keratinocyte proinflammatory response. Finally, it was demonstrated that erlotinib treatment alleviated carvacrol-induced dermatitis. These data demonstrate that erlotinib ameliorates skin inflammation by regulating Akt and NF-κB-mediated keratinocyte proinflammation, suggesting the therapeutic potential of erlotinib, a clinically used EGFR inhibitor, in skin inflammatory diseases.

A Phase 2 study of Savolitinib in Patients with MET Amplified Metastatic Colorectal Cancer.

MET amplification (amp) is a driver of acquired resistance to epidermal growth factor receptor (EGFR) antibodies in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). Savolitinib is an oral small molecule tyrosine kinase inhibitor that has demonstrated anti-tumor activity in MET-driven advanced solid tumors. We report the results of a phase 2 study of savolitinib in patients with mCRC with MET amp detected by circulating cell free (cf)DNA. Patients with chemotherapy refractory mCRC and MET amp detected by cfDNA were treated with savolitinib until unacceptable toxicity or disease progression. The primary endpoint was objective response rate. Secondary endpoints were clinical activity and safety. Five patients were enrolled and treated. Best overall response was stable disease (SD) in two patients, progressive disease (PD) in two patients, and one patient unevaluable for response. The majority of treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common TEAEs included fatigue (n = 3) and nausea (n = 3). There were no grade 4 or 5 TEAEs. Savolitinib was well tolerated; however, in this small group of biomarker-selected patients, we observed no evidence of anti-tumor activity. Clinicaltrials.gov Identifier: NCT03592641. Registered on July 17, 2018.

Esophageal ILC2s mediate abnormal epithelial remodeling in eosinophilic esophagitis via Areg-EGFR signaling.

Eosinophilic esophagitis (EoE) is a chronic allergic disorder characterized by eosinophilia and epithelial thickening, resulting in dysphagia. While emerging evidence implicates increased frequencies of group 2 innate lymphoid cells (ILC2s) and increased interleukin (IL)-33 expression in EoE pathogenesis, the precise mechanisms remain unclear. In this study, we investigated the role of ILC2s in EoE pathogenesis. We observed an abundance of KLRG1+ ILC2s in the esophagi of healthy mice, with their numbers significantly increasing in murine EoE models and humans. Using a murine EoE model, we demonstrated the recapitulation of EoE-associated features, including basal-cell hyperproliferation, epithelial thickening, and eosinophilia. Notably, these characteristics are absent in ILC-deficient mice, whereas mice lacking IL-5 or eosinophils display epithelial defects, highlighting the pivotal role of ILC2s in EoE pathogenesis. Further investigations revealed increased amphiregulin (Areg) production by esophageal ILC2s in mice. The administration of Areg induced epithelial defects similar to those observed in EoE. Mechanistic studies using human esophageal cell lines revealed Areg-induced phosphorylation of epidermal growth factor receptor (EGFR). Significatntly, treatment with anti-Areg agents and EGFR inhibitors effectively attenuated EoE development, highlighting the therapeutic potential of targeting the Areg-EGFR axis.

Clinicopathological significance of sulfite oxidase expression in surgically resected lung adenocarcinoma.

The coenzyme sulfite oxidase (SUOX), located in mitochondria, plays a role in redox and metabolism. Its expression has been associated with cancer progression and prognosis. Lung cancer has a high incidence rate and poor prognosis. We aim to clarify its expression in lung adenocarcinomas and investigated the utility of SUOX expression as a recurrence factor in operable lung adenocarcinoma. We used 60 formalin-fixed paraffin-embedded samples of operable primary lung adenocarcinoma between 2017 and 2018 to immunohistochemically assess SUOX expression levels. Patients were classified into a high or low SUOX expression group, and the associations of SUOX expression with clinicopathological findings and recurrence were analyzed. We revealed that high SUOX expression was significantly (p < 0.05) associated with sex, low Brinkman index, histological type, histological grade and positive for epidermal growth factor receptor (EGFR) mutation. High SUOX expression (HR = 10.218, 95% CI 1.758‒59.376, p = 0.0096) and pathological Stage (HR = 7.538, 95% CI 1.95‒29.14, p = 0.0034) were independently associated with relapse free survival. High SUOX expression may be a new indicator of recurrence risk in surgically resected lung adenocarcinomas.

Abstract IA017: Transferrin receptor targeting chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins in cancer

Abstract The membrane and extracellular proteome plays central roles in health and disease. Harnessing TfR1, a constitutive, rapidly internalizing receptor overexpressed in a broad spectrum of cancers, we developed Transferrin Receptor Targeting Chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins. In two applications, we show that TransTACs enabled the targeting of drug-resistant epidermal growth factor receptor (EGFR)-driven lung cancer and the reversible control of primary Chimeric Antigen Receptor (CAR)-T cells. TransTACs represent a promising new family of bifunctional antibodies for precise manipulation of membrane proteins and for targeted cancer therapy. Citation Format: Xin Zhou. Transferrin receptor targeting chimeras (TransTACs) for targeted degradation of membrane and extracellular proteins in cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA017.

Evaluation of cyclin-dependent kinase 4/6 inhibitor-induced serum creatinine elevations in patients with hormone receptor positive breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have improved the efficacy of endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) and are now used in both early-stage and metastatic disease. Recent case reports suggest that pseudo-serum creatinine (Scr) elevations are likely a class effect of CDK4/6i. This single-center retrospective analysis included patients aged ≥18 years who received at least one dose of palbociclib, ribociclib, or abemaciclib for the treatment of HR+/HER2- BC in the early or advanced setting. The primary objective was the incidence of pseudo-Scr elevation for each of the three agents. CDK4/6i-induced pseudo-Scr elevation was suspected when the Scr elevation could not be fully attributed to other causes. Secondary endpoints included the grade, onset, duration, and clinical consequences of pseudo-Scr elevation. 143 patients were included. Pseudo-Scr elevation was suspected in patients treated with palbociclib, ribociclib, or abemaciclib, with incidences of 16% (8/50), 14% (6/43), and 20% (10/50), respectively. Rates did not significantly differ between agents (p = 0.727). Among patients with CDK4/6i-induced pseudo-Scr elevation, all events were grade 1 (8.3%) or 2 (91.7%). The median onset from treatment initiation to first Scr elevation was 33.5, 42, and 21.5 days, for palbociclib, ribociclib, or abemaciclib, respectively. Pseudo-Scr elevation appears to be a class effect of CDK4/6i, with similar rates of Scr elevation observed across the three agents currently FDA approved.

Efficacy and safety of lenvatinib plus gefitinib in lenvatinib-resistant hepatocellular carcinomas: a prospective, single-arm exploratory trial

Lenvatinib, a multi-kinase inhibitor, has been approved as first-line treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. We have shown previously that lenvatinib and epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combination therapy overcomes lenvatinib resistance in HCC with high level of EGFR expression (EGFRhigh). We present here the results of a single-arm, open-label, exploratory study of lenvatinib plus the EGFR-TKI gefitinib for patients with HCC resistance to lenvatinib (NCT04642547; n = 30). Only patients with EGFRhigh HCC and progressive disease after lenvatinib treatment were recruited in the study. The most frequent adverse events of all grades were fatigue (27 patients; 90%), followed by rash (25 patients; 83.3%), diarrhea (24 patients; 80%), and anorexia (12 patients; 40%). Among 30 patients, 9 (30%) achieved a confirmed partial response and 14 (46.7%) had stable disease according to mRECIST criteria. Based on RECIST1.1, 5 (16.7%) achieved a confirmed partial response and 18 (60%) had stable disease. The estimated median progression free survival (PFS) and overall survival (OS) time were 4.4 months (95% CI: 2.5 to 5.9) and13.7 months (95% CI: 9.0 to NA), respectively. The objective response rate (ORR) of the patients in the present study compares very favorable to that seen for the two approved second line treatments for HCC (cabozantinib ORR of 4%; regorafenib ORR of 11%). Given that this combination was well-tolerated, a further clinical study of this combination is warranted.

The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer

Lung cancer has emerged as a highly aggressive malignancy posing a significant global health hazard, with a particular concern for the rising incidence and mortality of gene-altered non-small cell lung cancer (NSCLC). As the prevalence of NSCLC rises, the investigation and selection of tumor treatment techniques are gaining significance. The treatment of individuals with genetic mutations in advanced NSCLC has emphasized the application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Early and subsequent generations of EGFR-TKIs have demonstrated clinical efficacy in NSCLC patients carrying select genetic alterations. Osimertinib, a third-generation EGFR-TKI, has been sanctioned as the standard first-line therapy and is also utilized as a second-line option for individuals who develop the T790M resistance mutation following prior EGFR-TKI treatment. Approximately 10 to 30 percent of patients diagnosed with NSCLC exhibit EGFR mutations. This leads to abnormal activation of cancer genes and inactivation of tumor suppressor genes, resulting in poor prognosis for patients. This paper aims to analyze the development and resistance processes of EGFR inhibitors, thereby enhancing the comprehension of the resistance pathways to EGFR-TKIs.

Integration of Longitudinal and Transverse Radiomics from Ultrasound Images with Clinical Factors for HER-2 Status Prediction in Invasive Breast Cancer Patients

Objective This study developed a nomogram combining longitudinal and transverse ultrasound radiomics with clinical factors to identify human epidermal growth factor receptor 2 (HER2) status in invasive breast cancer (BC). Materials and methods We analyzed 537 invasive BC patients from two hospitals: 436 in the training cohort (Hospital A) and 101 in the test cohort (Hospital B). From longitudinal and transverse ultrasound planes, 788 radiomics features were extracted, with dimensionality reduced using least absolute shrinkage and selection operator regression. A radiomics nomogram integrating clinical predictors and radiomics scores (Rad-scores) was constructed. Results Fifteen and sixteen features from longitudinal and transverse ultrasound planes, respectively, were selected to generate Rad-scores, which differed significantly between HER2-positive and HER2-negative groups in both cohorts (p < 0.05). The combined radiomics model outperformed individual models with AUCs of 0.783 and 0.762 in the training and external test cohorts, respectively. Tumor size was an independent clinical predictor. The nomogram, incorporating Rad-scores and tumor size, achieved AUCs of 0.790 (training cohort) and 0.774 (test cohort). Decision curve analysis demonstrated its potential clinical utility. Conclusion A biplanar ultrasound radiomics nomogram effectively predicts HER2 status in invasive BC, potentially reducing the need for biopsies and supporting personalized treatment strategies.

SPTLC2 drives an EGFR-FAK-HBEGF signaling axis to promote ovarian cancer progression.

The epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with ovarian cancer (OC) progression. However, inhibition of EGFR signaling in OC patients achieved limited therapeutic effects, highlighting the need to define the mechanism of EGFR deregulation in OC development. Herein we showed that serine palmitoyltransferase long chain base subunit 2 (SPTLC2) acts as a positive regulator in the EGFR signaling pathway in OC. Phenotypically, depletion of SPTLC2 suppressed clonogenic growth and migration of OC cells in vitro and in ovo, as well as metastasis in OC xenograft models, whereas overexpression of SPTLC2 yielded opposite effects. Mechanistically, SPTLC2 drives an EGFR-FAK-HBEGF signaling axis via binding with EGFR. Notably, the serine palmitoyltransferase activity of SPTLC2 is critical for regulation of the EGFR-FAK-HBEGF signaling axis and activity in OC progression. Clinically, high SPTLC2 expression is associated with high-grade serous ovarian cancer and metastasis. Collectively, our findings establish an oncogenic role of SPTLC2 in OC growth and progression though upregulation of EGFR signaling and suggest that SPTLC2 represents a potential therapeutic target in EGFR-driven ovarian cancer patients.

Synergistic inhibitory effect of atmospheric pressure plasma and berberine on non‑small cell lung cancer cells via inducing apoptosis.

Non-small cell lung cancer (NSCLC) is a type of lung cancer, the incidence and mortality rate have been high, and the use of monotherapy is easy to make patients develop tolerance. Atmospheric pressure plasma (APP) is an emerging technology for killing cancer cells in recent years, and combination of berberine (BBR) mechanism has not been fully elucidated for NSCLC. The article's primary goal is to investigate the effect of combination on NSCLC and its associated characterization. Antiproliferative effects were detected by cell viability assay and colony formation, and flow cytometry analysis of apoptosis and cycling showed that the combination synergistically induced apoptosis. Then, extracellular reactive oxygen species (ROS)levels and DCFH-DA-based kits examined intracellular ROS levels, and their effects on mitochondrial membrane potential were measured. Study reveals that co-induced apoptosis is associated with ROS accumulation. Subsequently, Western blotting (WB) detected the expression of epidermal growth factor receptor (EGFR), and the important signaling pathway proteins Ras/ERK and AKT/mTOR. Results showed that it could downregulation of EGFR protein expression and inhibit of activation of ERK/AKT signaling pathways. Simultaneous wound healing assay and epithelial-to-mesenchymal transition (EMT) marker detection were performed for the assessment of migration and EMT ability of NSCLC cells. Combination therapy inhibited migration and EMT of NSCLC cells. The results of this study show that the combination can synergistically induce apoptosis of NSCLC by regulating ROS production. EGFR downregulation and AKT/ERK signaling pathway inhibition are linked to the synergistic effect.

Real-World Study of EGFR-TKI Rechallenge With Another TKI After First-Line Osimertinib Discontinuation in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: A Subset Analysis of the Reiwa Study.

First-line osimertinib is widely used to treat patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancers (NSCLC). In clinical practice, rechallenge therapy with another EGFR-tyrosine kinase inhibitor (TKI) is often performed after first-line TKI discontinuation owing to resistance or toxicity; however, the efficacy and toxicity of EGFR-TKI rechallenge after first-line osimertinib have not been adequately investigated. This study aimed to examine the efficacy and safety of EGFR-TKI rechallenge with another TKI. This multicenter prospective observational study enrolled patients with EGFR-mutated NSCLC who received first-line osimertinib and another EGFR-TKI as second- or third-line treatment between September 2018 and August 2020. Fifty-three patients received rechallenge with another EGFR-TKI in the second-line (n = 38, 71.7%) or third-line (n = 15, 28.3%) setting. The primary reason for first-line osimertinib discontinuation was toxicity in 32 (60.4%, 17 patients with pneumonitis) and disease progression in 20 (37.7%) patients. The most common rechallenge EGFR-TKI was afatinib (n = 24, 45.3%), followed by gefitinib (n = 16, 30.2%) and erlotinib (n = 8, 15.1%). The real-world time to treatment failure (rwTTF) was 7.3 months. The rwTTF for the toxicity discontinuation and progressive disease discontinuation groups was 9.3 months and 5.1 months, respectively, (HR 1.61, p = 0.119). EGFR-TKI rechallenge was discontinued due to toxicity in nine patients (17.0%), but no patient developed pneumonitis. EGFR-TKI rechallenge with another TKI is well tolerated in patients with EGFR-mutated NSCLC. Thus, it may be a useful treatment option after first-line osimertinib failure, especially after osimertinib discontinuation due to toxicity.