Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

Treatment of delayed fracture healing with Bushen Tiansui decoction: Analysis of active agents and targets using bioinformatics and network pharmacology analysis.

This study aims to utilize bioinformatics and network pharmacology to identify the active components of Bushen Tiansui decoction (BSTSD) and elucidate its molecular mechanisms and targets in promoting delayed fracture healing. Using various databases and tools, we identified 155 active compounds within BSTSD's herbal components. Key compounds such as eriodictyol and β-sitosterol were noted for their significant anti-inflammatory, antioxidant, and immunomodulatory effects, which are crucial for promoting fracture healing. Network analysis revealed compounds such as kaempferol and luteolin as having high centrality within the network, indicating their central role in the therapeutic effects of BSTSD. Gene ontology (GO) enrichment analysis highlighted that biological processes such as gland development and aging are vital for fracture healing. Cellular components like membrane rafts and microdomains are essential for maintaining cellular functions and signal transduction during bone repair. Molecular functions such as protein serine/threonine kinase activity play key roles in regulating bone cell proliferation, differentiation, and remodeling. KEGG pathway analysis identified critical pathways including prostate cancer, proteoglycans in cancer, lipid and atherosclerosis, EGFR tyrosine kinase inhibitor resistance, chemical carcinogenesis receptor activation, PI3K-Akt signaling pathway, hepatitis B, endocrine resistance, HIF-1 signaling pathway, and estrogen signaling pathway. Molecular docking results showed strong binding affinities between key compounds and target proteins, supporting the reliability of the network pharmacology predictions. This study provides a comprehensive understanding of the molecular mechanisms by which BSTSD promotes fracture healing, identifying active compounds and pathways that offer scientific bases for the clinical application of BSTSD and paving the way for further experimental validation and therapeutic development.

Non-small cell lung cancer treated with epidermal growth factor receptor inhibitors: the effect of concurrent medications on patient outcomes.

EGFR tyrosine kinase inhibitor (TKI)-induced rash can be alleviated with tetracyclines (TCN) and topical corticosteroids (TCS), whereas drugs for acid-related disorders (DARD) can affect EGFR TKI absorption. The present study investigated the concomitant use of TCNs, TCSs, and DARDs with EGFR-TKIs in non-small cell lung cancer (NSCLC) and whether these affect patient outcomes. We retrospectively collected data from all patients (n=1498) who had purchased for EGFR TKIs (erlotinib, gefitinib, and afatinib) in Finland between 2011-2020. Overall survival (OS) and time on treatment (ToT) were analyzed from the first EGFR TKI purchase. Early TCN purchases were registered in 298 (19.6%) patients; early TCS and DARD purchases were observed in 154 (10.1%) and 192 (12.9%) while similar percentages were detected in the EGFR mutant cohort. In the entire cohort, early purchase of TCSs and TCNs was associated with improved ToT, OS, and DARDs with inferior outcomes. In the multivariate analysis, TCSs retained their significance in ToT (HR, 0.78; 95% 0.66-0.94), TCNs in OS (HR, 0.73; 95% 0.63-0.84), and DARDs in both (HR, 1.28; 95% 1.091-1.495; HR, 1.19; 95% 1.01-1.41). In the EGFR mutant cohort, similar non-significant trends were observed for TCSs and DARDs. In the analysis according to EGFR TKI, erlotinib users had improved outcomes when early TCN or TCS purchases were registered, whereas DARDs were associated with worse outcomes among gefitinib users. Among EGFR-TKI-treated NSCLCs, the use of TCN, TCS, and DARD can affect treatment outcomes that should be considered in optimal patient care.

Cordycepin and Its Structural Derivatives Effectively Suppress the High Expression of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase in Breast Carcinomas: A Computational Drug Development Approach

Background: Breast cancer is a frequently diagnosed malignant disease and the primary cause of mortality among women with cancer worldwide. The therapy options are influenced by the molecular subtype due to the intricate nature of the condition, which consists of various subtypes. By focusing on the activation of receptors, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase can be utilized as an effective drug target for therapeutic purposes of breast cancer. Objectives: The objective of this study is to compare the underlying pharmacological properties of several modified agents to the parental Cordycepin to target and inhibit the EGFR tyrosine kinase high expression, and to discover the inhibitor with the highest affinity for this drug target to treat the breast cancer patients. Methods: The Maestro Application of Schrödinger Suite Paid Software was initially employed for conducting extra precision (XP) structure-based virtual screening to evaluate the binding affinity of the Cordycepin and its 500 structural derivatives with the EGFR tyrosine kinase protein structure. In addition, the anti-breast cancer activity of the chosen compounds was assessed by looking at their drug-likeness and ADMET characteristics using Lipinski's rule of five along with Quantitative structure- activity relationship (QSAR) validation, the prediction of cell line anti-cancer, as well as anti- breast cancer activity of top docked scored compounds. Subsequently, the Desmond paid software- based molecular dynamics simulations (MDS) were conducted for a duration of 100 nanoseconds on the promising candidates followed by the binding free energy estimation was performed utilizing MM-GBSA analysis. To determine the stability of the protein-ligand complex, root-meansquare deviation (RMSD), root-mean-square fluctuation (RMSF), protein-ligand interactions, and other necessary parameters were evaluated from the 100 ns MDS Trajectory. Results: Based on the overall analysis of our study, N (6)-octylamine adenosine (CID-194932) reported the optimum inhibitory potential against the EGFR tyrosine kinase protein, followed by Adenosine 5-monophosphate (CID-83862) and Cordycepin (CID-6303), which compared favorably to the control drug Vandetanib (CID-3081361). Conclusion: Consequently, these derivative compounds Cordycepin have the potential to be utilized as lead molecules in the development of highly effective and potent EGFR tyrosine kinase inhibitors for the treatment of breast cancer patients.

Fracture-healing effects of Rhizoma Musae ethanolic extract: An integrated study using UHPLC-Q-Exactive-MS/MS, network pharmacology, and molecular docking.

Fracture disrupts the integrity and continuity of the bone, leading to symptoms such as pain, tenderness, swelling, and bruising. Rhizoma Musae is a medicinal material frequently utilized in the Miao ethnic region of Guizhou Province, China. However, its specific mechanism of action in treating fractures remains unknown. This study aimed to elucidate the chemical constituents of the ethanol extract of Rhizoma Musae (EERM) and investigate its fracture-healing mechanism using network pharmacology. The chemical profile of EERM was characterized via UHPLC-Q-Exactive-MS/MS. Subsequently, a comprehensive network of compounds, targets, and pathways was constructed using network pharmacology approaches. The interactions between the active compounds of EERM and their targets were validated through molecular docking, molecular dynamics simulation and in vitro cell experiments. EERM contained 522 identified compounds. Topological analysis of the protein-protein interaction (PPI) network identified 59 core targets, including key proteins like AKT1, IL-6, and EGFR, known for their anti-inflammatory properties and ability to enhance bone cell proliferation and differentiation. Gene Ontology analysis indicated the involvement of EERM in biological processes such as peptidyl-serine phosphorylation, response to xenobiotic stimulus, and nutrient level regulation. KEGG analysis suggested that EERM's mechanism may involve signaling pathways such as PI3K-Akt, lipid and atherosclerosis, EGFR tyrosine kinase inhibitor resistance, and MAPK pathways. Molecular docking and molecular dynamics simulations results demonstrated a strong binding affinity between the main compounds of EERM and key targets. In vitro cell experiments demonstrate that EERM enhances cell proliferation by upregulating the expression levels of EGFR and STAT3, while simultaneously downregulating AKT1 and CASP3. This study investigates the potential active compounds of EERM and its key targets in regulating multiple pathways of fracture, leading to promoting bone cell proliferation. These results offer valuable insights for the future development and clinical application of Rhizoma Musae.

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

The optimal strategy for modern chemotherapy should be based on a comprehensive approach for cancer patients with cardiovascular diseases. Therefore, cardio-oncology has received increasing attention owing to the cardiotoxic effects of anti-cancer therapies. We aimed to evaluate 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. This study was based on the Diagnosis Procedure Combination (DPC) database of the Japanese Registry of All Cardiac and Vascular Diseases (JROAD). We identified 1328113 patients who were hospitalized for HF between April 2012 and March 2021. The propensity score (PS) was estimated using a logistic regression model, with chemotherapy as the dependent variable, and a clinically score-matched analysis of 11532 patients with HF with or without chemotherapy. The primary endpoint was readmission. Colon, lung, breast and prostate cancers accounted for >60% of all cancer types. After PS matching, readmission was significantly more frequently observed in patients with chemotherapy than those without [odds ratio (OR), 1.26; 95% confidence interval (CI) 1.17-1.36, P<0.01]. In particular, treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (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) caused a higher risk of readmission. Medical providers need to monitor and follow-up patients with HF, depending on the characteristics of the anti-cancer agents and types of cancer.

Network Pharmacology Approach and Experimental Verification to Explore the Anti-NSCLC Mechanism of Grifolic Acid

Lung cancer is the leading cause of cancer-related death. Non–small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and over 60% express wild-type EGFR (WT-EGFR); however, EGFR tyrosine kinase inhibitors (TKIs) have limited effect in most patients with WT-EGFR tumors. In this study, we applied network pharmacology screening and MTT screening of bioactive compounds to obtain one novel grifolic acid that may inhibit NSCLC through the EGFR-ERK1/2 pathway. Through the PPI network and machine learning, we identified two hub genes, EGFR and AKT1, as potential therapeutic targets. Molecular docking confirmed that the grifolic acid could effectively bind to the key target, EGFR. Using the NSCLC cell line NCI-H1781 as an in vitro model, we evaluated the effect of the drugs’ combination on viability, apoptosis, and clonogenicity capacity. In vitro studies showed that combined treatment decreased cell viability, increased activation PARP, and caused cell cycle redistribution and significantly greater inhibition of pEGFR and pAKT. This study not only provides new insights into the mechanism of grifolic acid against NSCLC but also important information and new research ideas for the discovery of anti-NSCLC compounds from natural products.

The Potential Role of sPD-L1 as a Predictive Biomarker in EGFR-Positive Non-Small-Cell Lung Cancer

Background/Objectives: A significant breakthrough in non-small-cell lung cancer (NSCLC) treatment has occurred with the introduction of targeted therapies and immunotherapy. However, not all patients treated with these therapies would respond to treatment, and patients who respond to treatment would acquire resistance at some time point. This is why we need new biomarkers that can predict response to therapy. The aim of this study was to investigate whether soluble programmed cell death-ligand 1 (sPD-L1) could be a predictive biomarker in patients with epidermal growth factor receptor (EGFR)-positive NSCLC. Materials and Methods: Blood samples from 35 patients with EGFR-mutated (EGFRmut) adenocarcinoma who achieved disease control with EGFR tyrosine kinase inhibitor (EGFR TKI) therapy were collected for sPD-L1 analysis. We analyzed sPD-L1 concentrations in 30 healthy middle-aged subjects, as a control population, to determine the reference range. Adenocarcinoma patients were divided into two groups, i.e., a group with low sPD-L1 (≤182.5 ng/L) and a group with high sPD-L1 (&gt;182.5 ng/L). Results: We found that progression-free survival (PFS) was 18 months, 95% CI (11.1–24.9), for patients with low sPD-L1 and 25 months, 95% CI (8.3–41.7), for patients with high sPD-L1. There was no statistically significant difference in PFS between the groups (p = 0.100). Overall survival (OS) was 34.4 months, 95% CI (26.6–42.2), for patients with low sPD-L1 and 84.1 months, 95% CI (50.6–117.6), for patients with high sPD-L1; there was also no statistically significant difference between the groups (p = 0.114). Conclusion: In our study, we found that patients with high sPD-L1 had numerically better PFS and OS, but this has no statistical significance. Further studies with a larger number of patients are needed to evaluate the role of sPD-L1 as a predictive biomarker in patients with EGFRmut NSCLC.

Study on mechanism of Spatholobi Caulis in the treatment of the hand-foot skin reaction induced by targeted drug therapy based on network pharmacology and molecular docking: An observational study.

Based on network pharmacology and molecular docking methods, this study explored its active compounds and confirmed its potential mechanism of action against Hand-foot skin reaction induced by tumor-targeted drugs. Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and UniProt Database were used to obtain the active ingredients and target proteins of Spatholobi Caulis. All hand-foot skin reaction (HFSR)-related targets were obtained with the help of the Human Gene Database, Online Mendelian Inheritance in Humans (OMIM), DisGeNET and DrugBank databases. Cytoscape 3.7.1 software was used to construct the active ingredient-target visualization network of Spatholobi Caulis, and the common target network of Spatholobi Caulis and HFSR. And through the BisoGenet plug-in in Cytoscape, PPI network topology analysis was performed. The Metescape database and online mapping tool platform were used for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes Genomes (KEGG) pathway enrichment analysis to identify the key pathways of Spatholobi Caulis. Finally, Autodock Vina software and PyMol 2.5 software were used for molecular docking verification. There were 24 active components of Spatholobi Caulis and 244 target genes, 1635 disease-related target genes, 51 common target genes of Spatholobi Caulis and Hand-foot skin reaction, and key targets included NTRK1, epidermal growth factor receptor (EGFR), APP, TP53, HSP90AB1, HSP90AA, CUL3, etc. GO functional analysis involved a total of 66 molecular functions, 39 cellular components, and 817 biological processes. KEGG pathway analysis found 154 related signaling pathways, mainly enriched in Pathways in cancer, Human cytomegalovirus infection, Kaposi arcoma-associated herpesvirus infection, panic cancer, EGFR tyrosine kinase inhibitor resistance, P13K-Akt signaling pathway, Proteoglycans in cancer, HIF-1 signaling pathway and Ras signaling pathway, etc. Molecular docking results showed that luteolin, the active component of Spatholobi Caulis, had a high affinity with EGFR. Medicagol, the active components of Spatholobi Caulis, is proved in the Hand-foot skin reaction induced by lung cancer targeted therapy by regulating multiple signaling pathways through EGFR. It is confirmed that the treatment of Hand-foot skin reaction has the characteristics of multi-component, multi-target and multi-pathway regulation.

Effects of EGFR-TKIs combined with intracranial radiotherapy in EGFR-mutant non-small cell lung cancer patients with brain metastases: a retrospective multi-institutional analysis

BackgroundPatients with non-small cell lung cancer (NSCLC) are prone to developing brain metastases (BMs), particularly those with epidermal growth factor receptor (EGFR) mutations. In clinical practice, treatment-naïve EGFR-mutant NSCLC patients with asymptomatic BMs tend to choose EGFR-tyrosine kinase inhibitors (TKIs) as first-line therapy and defer intracranial radiotherapy (RT). However, the effectiveness of upfront intracranial RT remains unclear.MethodsThis was a retrospective study including 217 patients from two institutions between January 2018 and December 2022. Clinical data of NSCLC patients with BMs who received EGFR-TKIs were collected. The patients were assigned to one of the three groups according to the therapeutic modality used: the upfront TKI + stereotactic radiosurgery (SRS) / fractionated stereotactic radiotherapy (fSRS) group (upfront TKI + SRS/fSRS ), the upfront TKI + whole-brain radiotherapy (WBRT) group (upfront TKI + WBRT) and the upfront TKI group.ResultsAs of March 8, 2023, the median follow-up duration was 37.3 months (95% CI, 32.5–42.1). The median overall survival (OS) for the upfront TKI + SRS/fSRS, upfront TKI + WBRT, and upfront TKI groups were 37.8, 20.7, and 24.1 months, respectively (p = 0.015). In subgroup analysis, the upfront TKI + SRS/fSRS group demonstrated longer OS compared to the upfront TKI + WBRT and upfront TKI groups in patients treated with first or second-generation EGFR-TKIs (p = 0.021) and patients with L858R mutation (p = 0.017), whereas no survival benefit was observed in three-generation EGFR-TKIs or 19del subgroup. In the multivariable analysis, metachronous BMs, EGFR L858R mutation and nonclassic EGFR mutation were identified as independent risk factors for OS, while a DS-GPA score of 2.0–4.0 was the only independent protective factor.ConclusionsThis study demonstrated that upfront addition of SRS/fSRS to EGFR-TKIs was associated with longer OS compared to upfront WBRT or upfront TKI alone in EGFR-mutant NSCLC patients with BMs. This improvement was more significant in patients with L858R mutation and those treated with first or second-generation EGFR-TKIs. Further research with a larger sample size is warranted.

Pharmacokinetics, mass balance, and metabolism of [14C]PLB1004, a selective and irreversible EGFR-TKI in humans.

PLB1004, developed by Beijing Avistone Biotechnology Co., Ltd., is a safe, highly selective, and efficient irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) employed in treating non-small-cell-lung-cancer (NSCLC). This study investigated its pharmacokinetics, mass balance, and metabolism in 6 healthy Chinese male subjects treated with 160mg (70 µCi) [14C]PLB1004. Following drug administration, samples of blood, urine and feces were collected for quantitative determination of total radioactivity and metabolites were identified through radioactivity detection coupled with UHPLC-MS/MS. Following drug administration, the median radioactive Tmax was 4.17h in plasma, with the average t1/2 of PLB1004-related components in plasma of approximately 54.3h. Over 264h post-administration, the average cumulative excretion among the six subjects was 95.01% of the administered dose, with 84.71% and 10.30% excreted in feces and urine, respectively. Nine metabolites were characterized and identified and the parent drug PLB1004 was detected in plasma, urine, and feces. Among these metabolites, M689 was the most prevalent one in plasma, urine, and feces, constituting 25.37% of the total plasma radioactivity, and 55.88% and 1.73% of the administrated dose in feces and urine, respectively. Fecal excretion emerged as PLB1004 excretion route, while urinary excretion via the kidneys served as the secondary route. The primarily metabolic pathways are oxidation, demethylation, dehydrogenation, and cysteine conjugation in humans.

Alternating Administration of Osimertinib for Leptomeningitis and Docetaxel Plus Ramucirumab for Lung Adenocarcinoma Resistant to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors: A Case Report.

Traditionally, leptomeningitis (LM) has been considered untreatable and terminal, but the development of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has significantly improved the prognosis of patients with EGFR mutations. However, non-LM lesions occasionally progress or recur, even when the LM is successfully controlled with EGFR-TKIs, and treatment of such cases remains unclear. We herein report a patient with advanced non-small-cell lung cancer (NSCLC) who was treated with an EGFR-TKI for LM and cytotoxic chemotherapy for EGFR-TKI-resistant pulmonary lesions. The patient survived for almost four years after the diagnosis of LM, suggesting that this treatment may be beneficial in advanced NSCLC with EGFR-TKI-sensitive LM and EGFR-TKI-resistant extracranial lesions.

Coccinic acid exhibits anti-tumor efficacy against NSCLC harboring EGFR L858R/T790M mutation via the EGFR/STAT3 pathway.

Epidermal growth factor receptor (EGFR) is a starring target for the treatment of non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been used to treat NSCLC patients with EGFR-activating mutations. However, most patients invariably develop resistance to these agents due to the occurrence of novel mutations at the EGFR kinase domain. There is an urgent need to develop more effective therapy strategies to provide more selection for patients with NSCLC. Coccinic acid was reported to exerts potential anti-tumor effects, but its mechanism has not been elucidated and warrants investigation. In this study, coccinic acid was shown to inhibit cell proliferation on cells harboring L858R/T790M mutant EGFR by suppressing p-EGFR and p-STAT3. It was also shown that coccinic acid promoted cell cycle distribution and showed a potent apoptosis-inducing efficacy. Further results in vivo assays demonstrated that coccinic acid reduced tumor growth of NCI-H1975 xenograft in nude mice via the EGFR/STAT3 signaling. Moreover, these effects are involving in the binding of coccinic acid to the EGFR extracellular domain. In conclusion, our finding demonstrated that coccinic acid may be utilized as a potential novel candidate for NSCLC with EGFR L858R/T790M mutation.

Effect of furmonertinib on the pharmacokinetics of rivaroxaban or apixaban in vivo.

Furmonertinib, a third generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), is used for non-small cell lung cancer (NSCLC). Rivaroxaban and apixaban are direct oral anticoagulants (DOACs) used for venous thromboembolism (VTE), which is a frequent comorbid with NSCLC. They are substrates of CYP3A4, P-gp and BCRP, whereas furmonertinib is an inhibitor of P-gp and BCRP. This study aimed to disclose the extent of effect of furmonertinib on the pharmacokinetics of rivaroxaban or apixaban. Rats were divided into four groups (n=6) that received rivaroxaban (group 1), furmonertinib and rivaroxaban (group 2), apixaban (group 3), furmonertinib and apixaban (group 4). The concentrations of drugs were measured by an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Furmonertinib increased the Cmax and AUC0-t of rivaroxaban by 1.66 and 2.07-fold, whereas decreased the CLz/F by 1.70-fold and Vz/F 1.27-fold. Furthermore, furmonertinib caused similar changes in apixaban pharmacokinetics. The pharmacokinetic results suggest that it is essential to alert the effect of furmonertinib on the pharmacokinetics of rivaroxaban or apixaban in clinical practice.

Study Protocol of the Korean EGFR Registry: A Multicenter Prospective and Retrospective Cohort Study in Nonsmall Cell Lung Cancer Patients With EGFR Mutation.

The provision of treatment for epidermal growth factor receptor (EGFR)-mutated nonsmall cell lung cancer (NSCLC) patients has increased in Korea. However, multicenter studies on the clinicopathologic dataset and treatment outcomes, using a large-scale dataset, have not been conducted. The current study is a prospective and retrospective multicenter observational cohort study that registers all stages of EGFR-mutated NSCLC patients. The Korean EGFR Registry was designed to enroll 2000 patients with all stages of EGFR-mutated NSCLC from 40 university hospitals across Korea. This study, encompassing both retrospective and prospective cohorts, aims to analyze clinical characteristics, treatment modalities, and outcomes in these patients. Data collection will include patient demographics, smoking history, quality of life assessments, pathological data, and treatment outcomes, with follow-up until December 2026. The primary endpoint is disease-free survival in patients who have undergone radical therapy (surgery and radiotherapy) or progression-free survival in those receiving targeted therapy (first, second, and subsequent lines), chemotherapy (first and subsequent lines), combination therapy, and palliative/maintenance therapy according to stages of EGFR-mutated NSCLC. The study will explore the diagnostic methods for EGFR mutations, clinical outcomes based on treatment modalities, and metastatic patterns in EGFR-mutated NSCLC patients. Moreover, it will investigate various aspects, including the safety and efficacy of a new third-generation EGFR tyrosine kinase inhibitor (TKI), lazertinib, approved for both first- and second-line treatments. This study is expected to provide valuable insights into the epidemiology, risk factors, progression, and treatment outcomes of EGFR-mutated NSCLC in Korea. The Korean EGFR Registry will contribute significantly to the understanding of the complex dynamics of EGFR-mutated NSCLC, aiding in the development of more effective and personalized treatment strategies.

Prevalence of EGFR Mutations in Patients With Resected Stage I to III Nonsquamous Non-Small Cell Lung Cancer: Results of India Cohort.

The spectrum of EGFR is inadequately researched in patients with early-stage non-small cell lung cancer (NSCLC) in India. EARLY-epidermal growth factor receptor (EGFR) India (ClinicalTrials.gov identifier: NCT04742192), as part of a noninterventional, real-world global study, evaluated the prevalence of EGFR mutations in early-stage NSCLC in India. Prospective data from adult patients with surgically resected stage IA to IIIB (American Joint Committee on Cancer eighth edition) NSCLC between March 2021 and October 2022 were analyzed. In addition to descriptive statistics, Fisher's exact test with Monte Carlo was used to determine the association between EGFR mutations and clinicodemographic parameters. Of 74 patients (median age, 57.0 [range, 33.0-77.0] years) enrolled from eight centers in India, 73.0% (54 of 74) were males, 56.1% (37 of 66) were nonsmokers, and 95.9% (71 of 74) had adenocarcinoma. The EGFR mutation prevalence was 26.0% (19 of 73), of which Exon-19 deletions were the predominant subtype (13, 68.4%) followed by Exon 21-L858R (4, 21.1%), Exon 20-T790M (1, 5.3%), and compound (1, 5.3%) mutations. Nearly half (48.6%, 36 of 74) of the patients underwent only surgical resection. The remaining 51.4% (38 of 74) of the patients were prescribed neoadjuvant (n = 12; 16.2%) and adjuvant (n = 31; 41.9%) systemic therapies, and one patient (1.4%) received radiotherapy along with systemic therapy. In 60 patients with stage IB to IIIB NSCLC, systemic therapies, mainly platinum-based chemotherapy, were prescribed in 36 (60.0%). Only 8.1% (6 of 74) of the patients were prescribed EGFR-tyrosine kinase inhibitor (TKI), of which two received neoadjuvant and four were planned for adjuvant EGFR-TKI. Two (2.7%) patients were prescribed adjuvant immunotherapy. The univariate analysis showed higher odds of EGFR mutation for females (odds ratio, 3.96; P = .017). EARLY-EGFR India results showed the prevalence of EGFR mutation to be 26%. The study emphasized the pressing need for up-front biomarker testing at diagnosis to ensure optimal and timely personalized treatment.

Discovery of N-substituted-2-oxoindolin benzoylhydrazines as c-MET/SMO modulators in EGFRi-resistant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide, poses a formidable challenge due to its heterogeneity and the emergence of resistance to targeted therapies. While initially effective, first- and third-generation EGFR-tyrosine kinase inhibitors (TKIs) often fail to control disease progression, leaving patients with limited treatment options. To address this unmet medical need, we explored the therapeutic potential of multitargeting agents that simultaneously inhibit two key signalling pathways, the mesenchymal-epithelial transition factor (c-MET) and the G protein-coupled receptor Smoothened (SMO), frequently dysregulated in NSCLC. By employing a combination of in silico drug repurposing and structure-based structure-activity relationship (SAR) studies, we identified and developed novel c-MET/SMO-targeting agents with antiproliferative activity against first- as well as third-generation EGFR-TKI-resistant NSCLC cells suggesting a synergistic effect arising from the simultaneous inhibition of c-MET and SMO.

Response to EGFR/NTRK/MET Co-Inhibition Guided by Paired NGS in Advanced NSCLC With Acquired EGFR L858R/T790M/C797S Mutations.

EGFR tyrosine kinase inhibitors (TKIs) have significantly improved clinical outcomes for patients with non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations. However, resistance to TKI therapy often develops due to secondary EGFR mutations or the activation of bypass signalling pathways. Next-generation sequencing (NGS) can efficiently identify actionable genetic alterations throughout treatment. MET amplification is a well-established off-target resistance mechanism. Additionally, rarer mechanisms, such as NTRK1 gene fusions, have been reported. This report highlights a case of a 58-year-old male diagnosed with bone-metastatic NSCLC harboring the EGFR L858R mutation. After receiving dacomitinib and almonertinib sequentially, plasma-based NGS revealed the emergence of EGFR T790M-trans-C797S mutations, prompting a switch to a combination therapy of almonertinib and gefitinib. Upon disease progression, repeat NGS identified EGFR T790M-cis&trans-C797S mutations and a novel POT1::NTRK3 fusion in the blood. The fusion retained a complete NTRK kinase domain without frameshift variants, making it a target for treatment. Larotrectinib was incorporated into the dual EGFR-TKI regimen, forming a triplet therapy. Although this resulted in grade 3 dermatitis, the condition resolved after discontinuing gefitinib. At multiorgan progression, matched tissue- and plasma-based NGS identified MET amplification. Subsequently, the patient was started on a triple-inhibition regimen targeting EGFR, NTRK, and MET, which achieved a partial response with favorable tolerability. This is the first reported case of a novel, targetable POT1::NTRK3 fusion as a potential off-target mechanism mediating EGFR-TKI resistance, occurring alongside MET amplification in a patient with NSCLC harboring acquired EGFR L858R/T790M/C797S mutations. Concomitant inhibition of EGFR, NTRK, and MET was safe and resulted in a significant response, underscoring the importance of precision medicine guided by matched NGS.

Orthoallosteric EGFR-TKIs: A New Paradigm in NSCLC Treatment Strategy Targeting the C797S Mutation.

The remarkable clinical success of third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has significantly advanced the treatment landscape for non-small-cell lung cancer (NSCLC). However, the emergence of the tertiary point mutation C797S poses a substantial obstacle to their clinical efficacy, leading to a dearth of FDA-approved targeted therapies for patients harboring this mutation. Addressing this pressing clinical challenge necessitates the development of novel therapeutic agents targeting the clinically challenging EGFR mutation. This review delves into the design strategies, antitumor activity, and crucial protein-drug interactions of recently introduced Orthoallosteric fourth-generation EGFR-TKIs. These inhibitors are distinguished by their ability to simultaneously engage both the canonical orthosteric (ATP) binding site and the allosteric site. By shedding light on these key aspects, the review serves as a valuable resource for medicinal chemists, empowering them to propel the advancement of fourth-generation EGFR inhibitors.

CKAP4 is a potential therapeutic target to overcome resistance to EGFR-TKIs in lung adenocarcinoma.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for non-small cell lung cancer (NSCLC) patients with EGFR mutations; however, drug resistance limits their efficacy. Cytoskeleton-associated protein 4 (CKAP4) has been linked to cancer progression, but its role in EGFR-TKI resistance remains unclear. This study investigates the clinical relevance of CKAP4 as a therapeutic target to overcome EGFR-TKI resistance in lung adenocarcinoma (LUAD) patients. GEO datasets were analyzed to identify 24 differentially expressed genes associated with EGFR-TKI resistance, with CKAP4 selected via functional annotation and scoring using the VarElect tool. The prognostic significance of CKAP4 was evaluated using public databases, and its upregulation was confirmed in osimertinib-tolerant H1975 cells through quantitative reverse transcription-polymerase chain reaction. Integrated bioinformatics analysis identified CKAP4 as strongly associated with EGFR-TKI resistance. Elevated CKAP4 expression was particularly linked to poorer clinical outcomes in LUAD patients. Notably, osimertinib-tolerant cells exhibited high CKAP4 expression, correlating positively with increased half-maximal inhibitory concentrations of EGFR-TKIs. LUAD patients with upregulated CKAP4 showed significantly reduced overall and relapse-free survival. This study underscores the prognostic value of CKAP4 in EGFR-mutated LUAD and highlights its potential as a therapeutic target to counter EGFR-TKI resistance.

TLE1 corepressor promotes gefitinib resistance in lung cancer A549 cells via E‑cadherin silencing.

As a putative lung specific oncogene, the transducin-like enhancer of split 1 (TLE1) corepressor drives an anti-apoptotic and pro-epithelial-mesenchymal transition (EMT) gene transcriptional programs in human lung adenocarcinoma (LUAD) cells, thereby promoting anoikis resistance and tumor aggressiveness. Through its survival- and EMT-promoting gene regulatory programs, TLE1 may impact drug sensitivity and resistance in lung cancer cells. In the present study, a novel function of TLE1 was uncovered as an inhibitor of the antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib in the human LUAD cell line A549, which exhibits moderate sensitivity to EGFR-TKI. While upregulation of TLE1 expression potently inhibited the proliferation inhibitory and apoptotic effects of gefitinib in A549 cells, downregulation of endogenous TLE1 in these cells enhanced their sensitivity to gefitinib. In experimentally derived gefitinib-resistant A549 cells (A549GR) that have acquired EMT, TLE1 expression is upregulated as compared with parental A549 cells, and acute ablation of TLE1 expression is sufficient to partially restore gefitinib sensitivity and attenuate EMT phenotype. Mechanistic studies showed that TLE1 confers gefitinib resistance in A549 cells in part via downregulation of E-cadherin, a known potentiator of EGFR-TKI sensitivity and apoptosis induction. Importantly, the TLE1/E-cadherin transcriptional axis is negatively regulated by gefitinib to trigger apoptosis via the Bcl-2-inhibitor of transcription 1 cell death pathway. In conclusion, these results indicate a novel role of TLE1 in modulating EGFR-TKI sensitivity in lung cancer cells via regulation of E-cadherin expression, and its upregulation may potentiate EGFR-TKI resistance in LUAD.