Egfr kinase

In the 21st century, there has been a dramatic shift in the diagnosis and management of non-small cell lung carcinoma (NSCLC), with an increasing use of minimally invasive tissue acquisition methods. Current treatments require morphologic subtyping and biomarker information in all cases. Determining such biomarkers is a continuously evolving field; current guidelines state that the determination of mutations on the Epidermal Growth Factor (EFGR), Kirsten Rat Sarcoma viral oncogene homolog (KRAS), Proto-oncogene B-Raf (BRAF), Human epidermal growth factor receptor 2 (HER2) and Anaplastic Lymphoma Kinase (ALK), genes as well as fusions on genes such as ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1), MET proto-oncogene, receptor tyrosine kinase (MET), RET proto-oncogene (RET), and the Neurotrophic Tyrosine Receptor Kinase (NTRK) family is mandatory...

Osimertinib is the current first-line treatment for EGFR-mutated NSCLC, however, patients frequently relapse due to acquired resistance mutations. Amivantamab is a bispecific antibody against EGFR and MET alterations. Lazertinib is a tyrosine kinase inhibitor active against EGFR mutations including common resistance mutations. The MARIPOSA trial was designed to study if the combination of amivantamab plus lazertinib in untreated epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients would provide improved progression-free survival...

BACKGROUND: HER3 (ErbB3), a member of the human epidermal growth factor receptor family, is frequently overexpressed in various cancers. Multiple HER3-targeting antibodies and antibody-drug conjugates (ADCs) were developed for the solid tumor treatment, however none of HER3-targeting agent has been approved for tumor therapy yet. We developed DB-1310, a HER3 ADC composed of a novel humanized anti-HER3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor payload (P1021), and evaluate the efficacy and safety of DB-1310 in preclinical models...

AIMS: This study was designed to develop a model for predicting bone mineral density (BMD) loss of the femur after total hip arthroplasty (THA) using artificial intelligence (AI), and to identify factors that influence the prediction. Additionally, we virtually examined the efficacy of administration of bisphosphonate for cases with severe BMD loss based on the predictive model. METHODS: The study included 538 joints that underwent primary THA. The patients were divided into groups using unsupervised time series clustering for five-year BMD loss of Gruen zone 7 postoperatively, and a machine-learning model to predict the BMD loss was developed...

PURPOSE: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) indicated for the treatment of EGFR mutated (EGFRm)-driven lung adenocarcinomas. Osimertinib significantly improves progression-free survival in first-line treated patients with EGFRm advanced NSCLC. Despite the durable disease control, the majority of patients receiving osimertinib eventually develop disease progression. EXPERIMENTAL DESIGN: ctDNA profiling analysis on-progression plasma samples from patients treated with osimertinib in both first (Phase 3, FLAURA trial) and second-line trials (Phase 3, AURA3 trial) revealed a high prevalence of PIK3CA/AKT/PTEN alterations...

Molecularly targeted therapy for receptor tyrosine kinases (RTKs) has faced limitations in gastric and gastroesophageal junction (G/GEJ) cancer except for HER2-targeted agents, possibly due to inappropriate assay selection that has hindered identification of sensitive patients, in addition to coexisting genetic abnormalities as well as intratumoral heterogeneity. Immunohistochemistry of RTKs has, thus, proved largely unsuccessful for patient selection, and detection of RTK gene amplification as a true oncogenic driver is problematic given the small numbers of affected individuals...

Among the most prevalent forms of cancer are breast, lung, colon-rectum, and prostate cancers, and breast cancer is a major global health challenge, contributing to 2.26 million cases with approximately 685,000 deaths worldwide in 2020 alone, typically beginning in the milk ducts or lobules that produce and transport milk during lactation and it is becoming challenging to treat as the tissues are developing resistance, which makes urgent calls for new multitargeted drugs. The multitargeted drug design provides a better solution, simultaneously targeting multiple pathways, even when the drug resists one, it remains effective for others...

Circular RNAs (circRNAs) play an important role in the development of acquired resistance to many anticancer drugs. We developed the Non-Small-Cell Lung Cancer (NSCLC) cell lines with acquired resistance to osimertinib, a third-generation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and evaluated the different expression profiles of circRNAs in osimertinib-sensitive and -resistant NSCLC cell lines using RNA sequencing (RNA-Seq). The expression of selected differentially expressed circRNAs was verified using quantitative real-time PCR (qRT-PCR) in paired osimertinib-sensitive and -resistant NSCLC cell lines, and in plasma samples of osimertinib-sensitive and -resistant NSCLC patients...

Epidermal growth factor receptor EGFR inhibitors are widely used as first line therapy for the treatment of non-small-cell lung cancer (NSCLC) in patients harboring EGFR mutation. However, the acquisition of a second-site mutation (T790 M) limited the efficacy and developed resistance. Therefore, discovery and development of specific drug target for this mutation is of urgent needs. In our study we used the ChemDiv diversity database for receptor-based virtual screening to secure EGFR-TK inhibitors chemotherapeutics...

Osimertinib is a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), acting as the first-line medicine for advanced EGFR-mutated NSCLC. Recently, the acquired resistance to osimertinib brings great challenges to the advanced treatment. Therefore, it is in urgent need to find effective strategy to overcome osimertinib acquired resistance. Here, we demonstrated that SREBP pathway-driven lipogenesis was a key mediator to promote osimertinib acquired resistance, and firstly found Tanshinone IIA (Tan IIA), a natural pharmacologically active constituent isolated from Salvia miltiorrhiza, could overcome osimertinib-acquired resistance in vitro and in vivo via inhibiting SREBP pathway-mediated lipid lipogenesis by using LC-MS based cellular lipidomics analysis, quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, flow cytometry, small interfering RNAs transfection, and membrane fluidity assay et al...

The alcohol extraction of P. sibiricum has exhibited significant inhibitory effects on the production of free radicals and the proliferation of non-small-cell lung carcinoma (NSCLC) A549 cells. Despite the diverse components found in alcohol extraction of P. sibiricum and its multiple targets, the active components and associated targets remain largely unidentified. Hence, there is a need for additional investigation into the pharmacodynamic elements and mechanisms of action. This study aimed to analyze and identify the components responsible for the anti-tumor activity of alcohol extraction from P...

Targeted therapy revolutionizes the treatment of non-small-cell lung cancer (NSCLC), harboring molecular change. Epidermal growth factor receptor (EGFR) mutations play a crucial role in the development of NSCLC, serving as a pivotal factor in its pathogenesis. We elucidated the mechanisms of resistance and potential therapeutic strategies in NSCLC resistant to the EGFR-tyrosine kinase inhibitor (EGFR-TKI). This is achieved by identifying rare missense variants through whole exome sequencing (WES). The goal is to enhance our understanding, identify biomarkers, and lay the groundwork for targeted interventions, thereby offering hope for an improved NSCLC treatment landscape...

OBJECTIVES: Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with MASH. Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARγ on CEACAM1 transcriptoin and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation...

Modern cancer treatment approaches aim at achieving cancer remission by using targeted and personalized therapies, as well as harnessing the power of the immune system to recognize and eliminate the cancer cells. To overcome a relatively short-lived response due to the development of resistance to the administered drugs, combination therapies have been pursued, as well. To expand the outlook of combination therapies, the objective of this study was to use high-throughput data generation technologies such as mass spectrometry and proteomics to investigate the response of HER2+ breast cancer cells to a mixture of two kinase inhibitors that has not been adopted yet as a standard treatment regime...

BACKGROUND/AIM: Glioblastoma is an extensively malignant neoplasm of the brain that predominantly impacts the human population. To address the challenge of glioblastoma, herein, we have searched for new drug-like candidates by extensive computational and biochemical investigations. METHOD: Approximately 950 compounds were virtually screened against the two most promising targets of glioblastoma, i.e., epidermal growth factor receptor (EGFR) and phosphoinositide 3-kinase (PI3K)...

Residual cancer cells persist even after targeted therapies, serving as a reservoir for the subsequent acquisition of genetic alterations that lead to acquired drug resistance and tumor relapse. These initial drug-tolerant persisters (DTP) are phenotypically heterogenous with transient phenotypes attributed to epigenetic, metabolic, and cell-cycle changes. DTPs are responsible for the inevitable relapse seen in EGFR-mutant non-small cell lung cancer (NSCLC) despite high initial response to tyrosine kinase inhibitor (TKI) treatment...

BACKGROUND: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear. OBJECTIVE: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis...

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab...

We investigated mRNA-lncRNA co-expression patterns in a cellular model system of non-small cell lung cancer (NSCLC) sensitive and resistant to the epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib/gefitinib. The aim of this study was to unveil insights into the complex mechanisms of NSCLC targeted therapy resistance and epithelial-to-mesenchymal transition (EMT). Genome-wide RNA expression was quantified for weighted gene co-expression network analysis (WGCNA) to correlate the expression levels of mRNAs and lncRNAs...

The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic...