Epidermal Growth Factor Receptor Tyrosine Research Articles

Clinical evaluation and outcome in patients with heart failure receiving chemotherapy with different anti-cancer agents

Abstract Background Over the last few decades, advances in cancer therapy have prolonged the life expectancies of patients diagnosed with malignancies. Although traditional cytotoxic chemotherapy, molecularly targeted therapy, and immunotherapy have improved survival rates, off-target adverse effects such as complications of the cardiovascular system require attention. The optimal strategy for modern chemotherapy should be based on a comprehensive approach for patients with cancer and cardiovascular diseases. Therefore, cardio-oncology has received increasing attention owing to the cardiotoxic effects of anti-cancer therapies. Purpose To assess the clinical characteristics and outcomes of patients with heart failure (HF) who received chemotherapy compared with those of a matched cohort with HF who did not receive chemotherapy, using real-world HF data. Methods This study used the Diagnosis Procedure Combination database of the Japanese Registry of All Cardiac and Vascular Disease. We identified 1,328,113 patients hospitalized for HF between April 2012 and March 2021. We excluded 14,043 patients with unknown outcomes, non-emergency admissions, and unknown chemotherapy data. The primary endpoint was readmission. Thus, our study included 5,774 patients who received chemotherapy and 39,412 patients who did not. The propensity score (PS) was estimated using a logistic regression model, with chemotherapy as the dependent variable, and clinically score-matched analysis of 11,532 patients with HF with or without chemotherapy. Results Colon, lung, breast, and prostate cancers accounted for > 60% of all cancer types. After PS matching, 62.5% and 19.5% of patients with HF had prostate and breast cancer, respectively. After PS matching, readmission was more frequently observed in patients undergoing chemotherapy than those not undergoing chemotherapy (odds ratio [OR], 1.26; 95% confidence interval [CI] 1.17–1.36, p<0.0001). Treatment with genomic epidermal growth factor receptor tyrosine kinase inhibitors (OR, 1.69; 95% CI 1.39–2.07), taxane (OR, 2.95; 95% CI 2.11–4.12), anthracyclines (OR, 1.86; 95% CI 1.19–2.90), and fluorouracil agents (OR, 1.65; 95% CI 1.18–2.30) resulted in a significant risk of readmission. Moreover, patients treated with endocrine therapy before hospitalization had significantly higher readmission rates than the matched patients who did not receive chemotherapy (aromatase inhibitors: OR, 1.40; 95% CI 1.19–1.65: anti-androgens: OR, 1.39; 95% CI 1.27–1.52: luteinizing hormone-releasing hormone agonists: OR, 1.18; 95% CI 1.08–1.30 and gonadotropin-releasing hormone antagonists: OR, 2.17; 95% CI 1.68–2.79). Conclusions Medical providers need to monitor and follow-up patients with HF, depending on the characteristics of the anticancer agents and types of cancer. Furthermore, close collaboration among oncologists, cardiologists, and healthcare professionals will ensure the delivery of optimal care for patients with HF undergoing chemotherapy.

The benefit and risk of addition of chemotherapy to EGFR tyrosine kinase inhibitors for EGFR-positive non-small cell lung cancer patients with brain metastases: a meta-analysis based on randomized controlled trials

BackgroundCombining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups.MethodsSix databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety.ResultsSeven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%).ConclusionsETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073.

MicroRNA-130a-3p regulates osimertinib resistance by targeting runt-related transcription factor 3 in lung adenocarcinoma

Overcoming resistance to epidermal growth factor receptor tyrosine kinase inhibitors, including osimertinib, is urgent to improve lung cancer treatment outcomes. Extracellular vesicle (EV)-derived microRNAs (EV-miRNAs) play important roles in drug resistance and serve as promising biomarkers. In this study, we aimed to identify EV-miRNAs associated with osimertinib resistance and investigate their clinical relevance. The release of excess EVs was confirmed in the osimertinib-resistant lung adenocarcinoma cell line PC9OR. The exposure of PC9OR-derived EVs and EV-miRNAs to PC9 cells increased cell viability after osimertinib treatment. Microarray analysis revealed that miR-130a-3p was upregulated in EVs derived from PC9OR cells and another osimertinib-resistant cell line (H1975OR). Transfection with miR-130a-3p attenuated osimertinib-induced cytotoxicity and apoptosis in both PC9 and H1975 cells, whereas osimertinib resistance in PC9OR cells was reversed after miR-130a-3p inhibition. Bioinformatics analysis revealed that runt-related transcription factor 3 is a target gene of miR-130a-3p, and it induced osimertinib resistance in PC9 cells. Patients with lower baseline serum miR-130a-3p concentrations had longer progression-free survival. miR-130a-3p is a potential therapeutic target and a predictive biomarker of osimertinib resistance in adenocarcinomas.

Hypertrophic cardiomyopathy-associated mutations drive stromal activation via EGFR-mediated paracrine signaling.

Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the left ventricular wall, diastolic dysfunction, and fibrosis, and is associated with mutations in genes encoding sarcomere proteins. While in vitro studies have used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to study HCM, these models have not examined the multicellular interactions involved in fibrosis. Using engineered cardiac microtissues (CMTs) composed of HCM-causing MYH7-variant hiPSC-CMs and wild-type fibroblasts, we observed cell-cell cross-talk leading to increased collagen deposition, tissue stiffening, and decreased contractility dependent on fibroblast proliferation. hiPSC-CM conditioned media and single-nucleus RNA sequencing data suggested that fibroblast proliferation is mediated by paracrine signals from MYH7-variant cardiomyocytes. Furthermore, inhibiting epidermal growth factor receptor tyrosine kinase with erlotinib hydrochloride attenuated stromal activation. Last, HCM-causing MYBPC3-variant CMTs also demonstrated increased stromal activation and reduced contractility, but with distinct characteristics. Together, these findings establish a paracrine-mediated cross-talk potentially responsible for fibrotic changes observed in HCM.

Optimal first-line treatment for EGFR-mutated NSCLC: a comparative analysis of osimertinib and second-generation EGFR-TKIs

BackgroundOsimertinib is an irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is the preferred first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC) compared to first-generation EGFR-TKIs. However, limited research has compared its clinical effectiveness with second-generation (2nd G) EGFR-TKIs.Materials and methodsThis study recruited patients diagnosed with stage IIIb-IV EGFR-mutated NSCLC who received first-line treatment with either 2nd G EGFR-TKIs (afatinib and dacomitinib) or osimertinib between April 2020 and April 2023.ResultsThe final analysis included 168 patients, of whom 113 received 2nd G EGFR-TKIs (afatinib or dacomitinib) and 55 received osimertinib. The median progression-free survival (PFS) did not differ significantly between 2nd G EGFR-TKIs and osimertinib (del 19: 17.6 months; L858R: 20.0 months vs. 28.3 months, p = 0.081). In patients with the EGFR exon 19 deletion, osimertinib conferred a longer median PFS (28.3 vs. 17.6 months, p = 0.118) and time to treatment failure (30.2 vs. 22.7 months, p = 0.722) than 2nd G EGFR-TKIs. However, the differences were not statistically significant. In patients with with the EGFR exon 19 deletion and central nervous system metastasis, the median PFS did not differ significantly between those treated with osimertinib (14.3 months) and those treated with 2nd G EGFR-TKIs (17.6 months; p = 0.881). Multivariate regression analysis revealed that the NSCLC stage was the only independent negative predictor of PFS. The treatment patterns in the second line also differed significantly between groups (p = 0.008).ConclusionsThis study found comparable effectiveness between osimertinib and 2nd G EGFR-TKIs as first-line treatment for advanced EGFR-mutated NSCLC, with only the NSCLC stage identified as a negative predictor of PFS. However, whether the different second-line treatments affect overall survival should be examined.

ARAF Amplification in Small-Cell Lung Cancer-Transformed Tumors Following Resistance to Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors

Background/Objectives: Although tyrosine kinase inhibitors (TKIs) targeting EGFR-activating mutations significantly improved the outcome of EGFR-mutant NSCLC, resistance inevitably emerges. Despite the heterogeneity of these resistance mechanisms, many induce activation of MAPK signaling in the presence of EGFR-TKIs. While ARAF gene amplification is identified as a resistance mechanism that activates MAPK signaling by directly interacting with RAS, little is known about its clinicopathologic characteristics. Methods: We conducted a single-center retrospective analysis of the presence of ARAF amplification in re-biopsied samples in patients with EGFR-mutant NSCLC resistant to EGFR-TKIs. Demographic data, treatment course, and clinical molecular testing reports were extracted from electronic medical records. ARAF amplification was determined using a gene copy number assay. RNA sequence analysis was performed in patients with ARAF amplification as well as presenting histologic transformations to small-cell lung carcinoma (SCLC). Results: ARAF amplification was identified in five of ninety-seven patients resistant to erlotinib or gefitinib, and four of forty-eight patients resistant to Osimertinib. ARAF amplification was dominantly observed in female patients with EGFR exon 19 deletion. All ARAF-amplified tumors retained their founder EGFR mutation and were absent of secondary mutations. Two cases were found where ARAF amplification correlated with a histological transformation to SCLC. Conclusions: ARAF amplification was identified in 5–8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.

Evaluation of the prognostic value of the new 9th edition Tumor-Node-Metastases (TNM) staging system for epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma patients with bone metastases

BackgroundThere are some changes in the new 9th edition Tumor-Node-Metastases (TNM) staging system for lung cancer, including subdividing M1c into M1c1 and M1c2 stage. The aim of this study was to assess the prognostic performance of the updated classification system and try to provide some real-world application data among advanced lung adenocarcinoma patients with bone metastases.MethodsAdvanced lung adenocarcinoma patients in M1c stage with bone metastases who receiving first-line first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and T790M-guided osimertinib as the second-line therapy were retrospectively screened from December 2016 to December 2021. A total of 126 patients were enrolled in this study. 62 patients and 64 patients were subdivided into M1c1 and M1c2 groups according to the 9th edition of TNM staging system.The first-line real-world progression-free survival (1LrwPFS), the second-line real-world progression-free survival (2LrwPFS), post-progression survival (PPS) and real-world overall survival (rwOS) were analyzed.ResultsThe overall median rwOS was 40.1 months (95% CI 35.996–44.204). 1LrwPFS was 13.9 months (95% CI 12.653–15.147) and 2LrwPFS was 14.5 months (95% CI 11.665–17.335) for all patients.Patients in M1c2 stage was inferior to M1c1 stage patients in rwOS (35.2 months vs. 42.9 months, HR = 0.512, P = 0.005). 2LrwPFS was moderately correlated with rwOS (r = 0.621, R2 = 0.568, P = 0.000). Multivariate analysis showed performance status (PS) score ≥ 2 and TP53 alteration positive were independent prognostic factors of worse rwOS.ConclusionsMore refined stratification of M1c according to the 9th edition of TNM staging system is conducive to the judgment of prognosis and the implementation of precision medicine for patients.

Scientific substantiation of the maximum permissible concentration of the pharmaceutical substance osimertinib mesylate in the air of the working area

Introduction. Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor, is currently the only drug registered for the treatment of metastatic non-small cell lung cancer in patients with a positive T790M mutation status. The production of osimertinib mesylate is planned on the territory of the Russian Federation, which necessitates research to substantiate the hygienic standard for the aerosol content of the substance in the air of the working area. Conducting research to substantiate the maximum permissible concentration of a substance requires significant material and time resources, while using the results of preclinical and clinical studies, mathematical modeling of processes, and risk assessment methodology allows for a comprehensive assessment of the substance, while significantly reducing the time and cost of work. The study aims to scientifically substantiate the maximum permissible concentration of the pharmaceutical substance osimertinib mesylate in the air of the working area using data from toxicological studies and mathematical modeling of the effects of the substance on humans in industrial conditions. Materials and methods. The materials used were domestic and international databases, reports, research protocols, scientific articles and monographs containing information on the physico-chemical and toxic properties, pharmacotherapeutic activity of osimertinib. Results. The specialists have conducted hygienic regulation of osimertinib, taking into account data on its toxicity, danger, pharmacotherapeutic activity, side effects, long-term consequences, pharmacokinetic studies and modeling. To substantiate the value of the maximum permissible concentration, the authors used the reference points: an inactive NOEL level of 1 mg/­kg/­day for general toxic effect, established in a 92-day experiment on rats with intragastric administration; the lowest observed level of adverse effects of LOAEL is 0.5 mg/kg/day for general toxic effect, established in a 180-day experiment on dogs with intragastric administration; the level that does not cause adverse effects of NOAEL is 10 mg/kg/day for general toxic effect, established in a 180-day experiment on mice with intragastric administration. Safe concentrations of osimertinib in the air of the work area were evaluated using reference points, including the pharmacological effect and the minimum daily therapeutic dose; toxicokinetic modeling of concentrations of a substance in the human body under production conditions and the level of minimal risk. Limitation. The study is limited to the review of open literature sources describing the toxicological/toxicokinetic characteristics of osimertinib mesylate. Conclusion. The most stringent indicators of safe exposure levels, established on the basis of pharmacological effect and toxicokinetic modeling in dogs, allowed us to recommend 0.005 mg/m3, aerosol, hazard class 1 as the maximum permissible concentration in the air of the working area for osimertinib mesylate. Ethics. This study did not require the conclusion of the Ethics Committee.

Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.

Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy. Eligible patients were aged ≥ 20years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters. This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9months; estimated survival rates at 12, 24, and 36months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240mg/day was consistent with previous findings. Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes. ClinicalTrials.gov identifier NCT03046992.

Thoracic Radiotherapy Improves the Survival in Patients With EGFR-Mutated Oligo-Organ Metastatic Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors: A Multicenter, Randomized, Controlled, Phase III Trial.

This multicenter, randomized, phase III clinical trial (Northern Radiation Oncology Group of China-002) focused on patients with oligo-organ metastatic non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. We aimed to investigate whether first-line concurrent thoracic radiotherapy (TRT) and EGFR-tyrosine kinase inhibitors (TKIs), compared with TKIs alone, could achieve better survival. The patients in the TKI plus TRT group received 60 Gy to primary lung tumor and positive regional lymph nodes. Radiotherapy for metastases to other sites was determined by clinicians. The primary end point was the progression-free survival (PFS). Secondary end points included overall survival (OS) and treatment-related adverse events (TRAEs). The first and second interim analyses were performed in March 2021 and March 2022. Between April 14, 2016, and February 25, 2022, a total of 118 patients were enrolled. Compared with the TKI alone group, the TKI plus TRT group achieved significantly better PFS (hazard ratio [HR], 0.57; P = .004) and OS (HR, 0.62; P = .029). The median PFS was 10.6 months in the TKI alone group and 17.1 months in the TKI plus TRT group. The median OS was 26.2 months and 34.4 months in the TKI alone group and TKI plus TRT group, respectively. The TKI plus TRT group showed better local control but was associated with a higher incidence of severe TRAEs (11.9% v 5.1%). For patients with EGFR-mutated oligo-organ metastatic NSCLC treated with first-line EGFR-TKIs, concurrent TRT improves the PFS and OS, and TRAEs are acceptable and tolerable.

Risk of COVID-19 infection in patients with NSCLC receiving EGFR-TKI targeted therapy during the first wave in China.

We examined the factors influencing hospitalization and prognosis among patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeted therapy during the first wave of the coronavirus disease 2019 (COVID-19) pandemic. In total, 267 patients diagnosed with NSCLC who were receiving treatment with third-generation EGFR-TKIs were included in our retrospective study. Data on patients' demographics, clinical characteristics, and survival were collected and analyzed. Over a mean follow-up of 18 months, 80.5% (215/267) of the patients contracted COVID-19, and 12.6% (27/215) of these patients were hospitalized for COVID-19 treatment. Vaccinated patients, those with body mass index (BMI) ≥22.3 kg/m2, and those with no comorbidities had lower rates of infection and hospitalization than unvaccinated patients, those with BMI <22.3 kg/m2, and those with comorbidities, respectively. Continued NSCLC treatment in patients with COVID-19 was identified as a risk factor for patient survival. NSCLC treatment can be continued for patients who received COVID-19 vaccines, those with higher BMI, and those without comorbidities during the COVID-19 epidemic, but treatment interruption might be required for patients during the active phase of infection.

Initial AXL and MCL-1 inhibition contributes to abolishing lazertinib tolerance in EGFR-mutant lung cancer cells.

Lazertinib, a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), demonstrates marked efficacy in EGFR-mutant lung cancer. However, resistance commonly develops, prompting consideration of therapeutic strategies to overcome initial drug resistance mechanisms. This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells.

Combined inhibition of MET and VEGF enhances therapeutic efficacy of EGFR TKIs in EGFR-mutant non-small cell lung cancer with concomitant aberrant MET activation

Abstract Background Aberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined. Methods The gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo. Results We successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR/MET co-altered case. Conclusions Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.

Strategies and influencing factors for the treatment of advanced non-small cell lung cancer based on epidermal growth factor receptor tyrosine kinase inhibitors: a narrative review.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the primary treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, significantly enhancing patient prognosis. Despite the efficacy of EGFR-TKIs, monotherapy faces challenges such as variability among individuals and early drug resistance. This article aims to explore the treatment strategies and influencing factors for advanced NSCLC patients treated with EGFR-TKIs, optimize treatment plans, and improve the prognosis of patients with advanced NSCLC. We undertook a comprehensive, narrative review of the latest literature to define the current application and progress of EGFR-TKIs in treating patients with advanced NSCLC. The efficacy and promise of EGFR-TKIs, both as monotherapy and combined with other agents, for treating patients with advanced NSCLC are outlined. The study delves into the mechanisms of resistance and the ongoing development of EGFR-TKIs. Various factors influencing the treatment of advanced NSCLC patients with EGFR-TKIs are also examined. EGFR-TKIs alone improve survival in patients with advanced NSCLC. Combined with other agents, some regimens have shown improved benefits in overcoming drug resistance and prolonging patient survival. It is imperative to focus on developing novel EGFR-TKIs and investigate innovative combination therapies to maximize patient benefit.

An "AND" logic gate-based supramolecular therapeutic nanoplatform for combatting drug-resistant non-small cell lung cancer.

Despite targeted therapies like epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), non-small cell lung cancer (NSCLC) remains a clinical challenge due to drug resistance hampering their efficacy. Here, we designed an "AND" logic gate-based supramolecular therapeutic platform (HA-BPY-GEF-NPs) for the treatment of EGFR-TKI resistant NSCLC. This system integrates both internal and external stimuli-responsive mechanisms that need to be activated in a preset sequence, enabling it to precisely control drug release behavior for enhancing therapeutic precision. By programming the system to respond to sequential near-infrared (NIR) irradiation and enzyme (cathepsin B) inputs, the release of gefitinib is effectively confined to the tumor region. Moreover, the NIR irradiation induces reactive oxygen species production, suppressing tumor growth and inhibiting bypass signaling pathways. The designed drug delivery system offers a highly controlled and targeted therapeutic approach, effectively inhibiting tumor growth, suppressing bypass signaling pathways, and overcoming EGFR-TKI resistance, thus offering a potential solution for maximizing therapeutic benefits.

Successful rapid improvement of acute respiratory distress syndrome induced by EGFR-mutated non-small cell lung cancer with almonertinib: a case report

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening condition frequently encountered in critically ill patients, including those with advanced non-small cell lung cancer (NSCLC). Almonertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has shown promise as a first-line treatment for NSCLC with classical EGFR mutations. However, its efficacy in NSCLC patients suffering from ARDS has not been well-documented.Case PresentationWe report the case of a 63-year-old Chinese Han female with severe NSCLC complicated by ARDS. Upon hospital admission, the patient exhibited progressive dyspnea and required intubation to maintain oxygenation. Pathological analysis of bronchoalveolar lavage fluid sediment confirmed lung adenocarcinoma, and genetic testing of blood identified an EGFR E19 mutation. The patient was treated with almonertinib, resulting in significant clinical improvement and successful extubation after nine days. Radiographic imaging showed substantial reduction in pulmonary lesions, highlighting the efficacy of almonertinib.ConclusionThis case represents the first documented successful treatment of ARDS induced by EGFR E19 mutated NSCLC using almonertinib. The favorable clinical response observed in this critically ill patient suggests that almonertinib may be a viable therapeutic option for managing severe complications in NSCLC. Further research is necessary to corroborate these findings and optimize dosage and toxicity management strategies for broader clinical application.

Pharmacological targets and validation of remdesivir for the treatment of COVID-19-associated pulmonary fibrosis: A network-based pharmacology and bioinformatics study.

The objective of this study was to employ bioinformatics and network pharmacology methodologies to investigate the targets and molecular mechanisms of remdesivir in the treatment of coronavirus disease 2019 (COVID-19)-associated pulmonary fibrosis (PF). Several open-source databases were utilized to confirm the shared targets of remdesivir, COVID-19, and PF. Following this, a comprehensive analysis incorporating function enrichment, protein-protein interaction (PPI), transcription factor (TF), and molecular docking was conducted to investigate the potential mechanisms underlying the effectiveness of remdesivir in the treatment of COVID-19-associated PF. The initial validation of these findings was performed using publicly available histological and single-cell sequencing databases. The functional enrichment analysis revealed a strong association between remdesivir and viral defense, inflammatory response, and immune response. The key pathways identified in the study were transforming growth factor (TGF-β), PI3K-Akt, mTOR, MAPK, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance, HIF-1, and Toll-like receptor signaling pathways. Additionally, the PPI analysis demonstrated the network relationships of 13 important targets, while the TF analysis provided valuable insights into the regulatory networks of these targets. Among the identified TFs, RELA was found to be the most significant. To validate our findings, we utilized publicly available histological and single-cell sequencing databases, successfully confirming the involvement of 8 key targets, including AKT1, EGFR, RHOA, MAPK1, PIK3R1, MAPK8, MAPK14, and MTOR. Furthermore, molecular docking studies were conducted to assess the interaction between remdesivir and the identified key targets, thus confirming its effective targeting effects. Remdesivir has the potential to exert antiviral, anti-inflammatory, and immunomodulatory effects in the context of COVID-19-associated PF.

Two major bovine milk whey proteins induce distinct responses in IEC-6 intestinal cells

Abstract α-Lactalbumin (α-LA) and β-lactoglobulin (β-LG) are major whey proteins in bovine milk. We studied the effects of these molecules on the intestinal cell response by comparing the native form with the denatured form containing oligomers obtained by treatment with 2,2,2-trifluoroethanol (TFE). We previously reported that proteins in native and TFE-treated forms exhibited cell growth stimulation and cytotoxicity, respectively, in undifferentiated rat crypt IEC-6 and human colon Caco-2 cells. However, neither whey protein showed cytotoxicity even in the TFE-treated form in differentiated Caco-2 cells. Only undifferentiated immature intestinal cells can distinguish between these native and denatured proteins. Moreover, α-LA and β-LG exhibited different oligomer formation characteristics during the TFE treatment. In the present study, we compared the effects of native and TFE-treated whey proteins on IEC-6 cells in more detail. The native forms of both whey proteins exhibited cell proliferative effects in a concentration-dependent manner. For the TFE-treated forms, α-LA showed rapid and potent cytotoxicity, whereas β-LG altered cell responses depending on its concentration and exposure time; lower concentration/shorter exposure and higher concentration/longer exposure induced cell growth stimulation and cytotoxicity, respectively. Pre-treatment of the cell membrane with cholesterol suppressed the effects on the cell response only in TFE-treated β-LG (TFE-β-LG). In a preliminary examination using inhibitors of signal transduction, TFE-treated α-LA acted on the intrinsic apoptosis pathway via Bcl-2-associated X and p53, whereas the action of TFE-LG did not require this pathway. Tyrosine phosphorylation is necessary for the cell proliferation effect of both native whey proteins; however, native α-LA, but not native β-LG, also required activation of the pathway with selective epidermal growth factor receptor tyrosine kinase and Janus kinase 2/3. In summary, the two major bovine milk whey proteins induced similar yet discrete responses in undifferentiated intestinal cells. Even when oligomers are formed, β-LG may be much less hazardous to immature intestinal cells than α-LA.

Abstract C021: Racial and socioeconomic disparities in molecular diagnostics for NSCLC patients

Abstract Background: Targeted therapies have substantially changed the landscape of non-small cell lung cancer (NSCLC) outcomes. These drugs work by inhibiting specific molecular pathways, such as the epidermal growth factor receptor (EGFR) tyrosine kinase, the anaplastic lymphoma kinase (ALK), KRAS, and BRAF oncogenic pathways. Approximately 30% of NSCLC patients will have tumors with eligible targetable mutations, but a molecular test must be conducted to assess eligibility to these treatments. Disparities in molecular testing could be partially responsible for the disproportionate utilization of targeted therapy across race and socioeconomic status (SES). Methods: Surveillance, Epidemiology and End Results (SEER)-Medicare linked data was queried for NSCLC patients diagnosed from 2013 (the first year that standard guidelines for molecular testing in lung cancer were available) to 2016. Patients were limited to age over 66 years at diagnosis with continuous Part A and B coverage and no Part C coverage, for 1 year prior and 90 days post-diagnosis. The primary outcome was receipt of a molecular test based on claims data. Race, defined as white, Black or other, was the primary predictor variable. Demographic and clinical characteristics of those receiving vs not receiving a molecular test were compared using χ2 tests for categorical variables and t-tests for continuous variables. We also performed multivariable logistic regression to assess the association of molecular testing with race adjusting for sex, age, marital status, Charlson comorbidity index, histology, tumor site, stage, and census-level poverty indicator. Results: There were 28,511 NSCLC patients, of which 9,639 (33.8%) received some type of molecular testing. Black patients were significantly less likely than white patients to have received a molecular test (p&amp;lt;0.0001). Only 23.9% of Black patients underwent any molecular testing, compared to 34.6% of white patients. Patients living in census tracts with at least 10% of residents living in poverty were also less likely to receive a molecular test (p&amp;lt;0.0001). Patients who were female (p&amp;lt;0.0001), married (p&amp;lt;0.0001), with fewer comorbidities (p&amp;lt;0.0001), adenocarcinoma histology (p&amp;lt;0.0001), tumors located in the lower lobe (p&amp;lt;0.0001), diagnosed at a later stage (p=0.0001) were more likely to have molecular testing. After adjustment, Black patients (ORadj [odds ratio]: 0.65; 95% CI [confidence interval]: 0.59-0.72) and those living in areas with greater poverty (ORadj: 0.87; 95% CI: 0.82-0.91) were statistically significantly less likely to have received molecular testing. Conclusions: Disparities exist in comprehensive molecular diagnostics, and could explain, at least in part, the high mortality observed among Black NSCLC patients. Addressing barriers to molecular testing could increase uptake of targeted therapy treatment, decreasing disparities and improving patient outcomes. Citation Format: Stephanie Tuminello, Wiley Turner, Matthew Untalan, Raja Flores, Emaneula Taioli. Racial and socioeconomic disparities in molecular diagnostics for NSCLC patients [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C021.

Integrating network pharmacology and bioinformatics to explore the mechanism of Xiaojian Zhongtang in treating major depressive disorder: An observational study.

Major depressive disorder (MDD) is a common mental illness. The traditional Chinese medicine compound Xiaojian Zhongtang (XJZT) has a good therapeutic effect on MDD, but the specific mechanism is not clear. The aim of this study is to explore the molecular mechanism of XJZT in the treatment of MDD through network pharmacology and bioinformatics. The traditional Chinese medicine system pharmacology database was used to screen the chemical components and targets of XJZT, while the online Mendelian inheritance in man, DisGeNET, Genecards, and therapeutic target database databases were used to collect MDD targets and identify the intersection targets of XJZT and MDD. A "drugs-components-targets" network was constructed using the Cytoscape platform, and the STRING was used for protein-protein interaction analysis of intersecting targets. Gene Ontology and Kyoto encyclopedia of genes and genomes analysis of intersecting targets was performed using the DAVID database. Obtain serum and brain transcriptome datasets of MDD from the gene expression omnibus database, and perform differentially expressed genes, weighted gene co-expression network analysis, gene set enrichment analysis, and receiver operating characteristic analysis. A total of 127 chemical components and 767 targets were obtained from XJZT, among which quercetin, kaempferol, and maltose are the core chemical components, and 1728 MDD targets were screened out, with 77 intersecting targets between XJZT and MDD. These targets mainly involve AGE-RAGE signaling pathway in diabetic complexes, epidermal growth factor receptor tyrosine kinase inhibitor resistance, and HIF-1 signaling pathway, and these core targets have strong binding activity with core components. In addition, 1166 differentially expressed genes were identified in the MDD serum transcriptome dataset, and weighted gene co-expression network analysis identified the most relevant gene modules (1269 genes), among which RAC-alpha serine/threonine-protein kinase (AKT1), D(4) dopamine receptor (DRD4), and kynurenine 3-monooxygenase (KMO) were target genes for the treatment of MDD with XJZT, these 3 genes are mainly related to the ubiquitin-mediated proteolysis, arachidonic acid (AA) metabolism, and Huntington disease pathways, and the expression of AKT1, DRD4, and KMO was also found in the MDD brain transcriptome dataset, which is significantly correlated with the occurrence of MDD. We have identified 3 key targets for XJZT treatment of MDD, including AKT1, KMO, and DRD4, and they can be regulated by the key components of XJZT, including quercetin, maltose, and kaempferol. This provides valuable insights for the early clinical diagnosis and development of therapeutic drugs for MDD.