Growth Factor Receptor Tyrosine Kinase Research Articles

Downregulation of AATK enhances susceptibility to ferroptosis by promoting endosome recycling in gefitinib-resistant lung cancer cells.

Ferroptosis has been characterised by disruption of the cell membrane through iron-related lipid peroxidation. However, regulation of iron homeostasis in lung cancer cells that are resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains unclear. Transcriptome analysis identified a significant downregulation of apoptosis-associated tyrosine kinase (AATK) mRNA expression in gefitinib-resistant PC9 (PC9-GR) cells, which were found to be more susceptible to ferroptosis inducers. An in-depth analysis of publicly available datasets revealed that downregulation of AATK mRNA was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. Knockdown of AATK-sensitised PC9, HCC827, and H441 cells to the ferroptosis inducer RSL3, whereas ectopic expression of AATK reduced RSL3-induced cell death in PC9-GR and HCC827-GR cells. Compared to PC9 cells, PC9-GR cells exhibited higher transferrin uptake, endosome recycling rate, and increased intracellular iron levels. Blocking iron transport reduced RSL3-induced ferroptosis in PC9-GR cells. Mechanistic studies showed that AATK localised to both early and recycling endosomes. Knockdown of AATK facilitated endosome recycling and elevated intracellular ferrous iron (Fe2+) levels in PC9 cells. Conversely, ectopic expression of AATK delayed endosome recycling and reduced intracellular Fe2+ levels in PC9-GR cells. Inhibition of AATK downregulation-induced iron accumulation decreased RSL3-induced ferroptosis. Taken together, our study indicates that the downregulation of AATK contributes to endosome recycling and iron accumulation, leading to an increased susceptibility to ferroptosis in EGFR-TKI-resistant lung cancer cells. © 2025 The Pathological Society of Great Britain and Ireland.

Population pharmacokinetics of erlotinib in patients with non-small cell lung cancer (NSCLC): A model-based meta-analysis.

Erlotinib is a potent first-generation epidermal growth factor receptor tyrosine kinase inhibitor. Due to its proximity to the upper limit of tolerability, dose adjustments are often necessary to manage potential adverse reactions resulting from its pharmacokinetic (PK) variability. Population PK studies of erlotinib were identified using PubMed databases. Simulations of erlotinib concentrations were conducted at 4-h intervals, with covariate simulations based on patient characteristics. Three studies were included in this analysis. The one-compartment model was determined to be the most suitable for describing the population PK of erlotinib. A decrease in clearance was observed with age, while an increase in clearance was noted in smoking patients. The volume of distribution was positively correlated with body weight. Our study proposes optimal dosing of erlotinib based on age and smoking status, categorizing the patient population into six groups. This is the first report on a model-based meta-analysis approach to develop a population PK model of erlotinib in patients with non-small cell lung cancer. Our findings suggest that an increased dosage is appropriate for patients under 60 who smoke, whereas a reduced dosage is more suitable for non-smoking older patients.

Pharmacovigilance imbalance analysis of VEGFR-TKI-related taste and smell disorders

Taste and smell disorders (TSDs) can induce diminished interest in food, inadequate nutrient intake, and emotional irregularities, particularly among cancer patients. Previous research found that the main culprits of TSD development in cancer patients are cytotoxic drugs such as taxol, fluorouracil, cyclophosphamide, and anthracycline-based drugs. The advent of targeted drugs such as vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) has significantly extended the survival time of cancer patients, and thus widely used in clinical practice. However, the association between the use of VEGFR-TKIs and the development of TSDs havs not been studied.The adverse event(AE) reports related to VEGFR-TKIs were downloaded from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis was conducted to assess the correlation between VEGFR-TKIs and TSDs. The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) were used to analyze the AEs of TSDs. The study found a statistically significant correlation between the occurrence of TSDs and the use of VEGF-TKIs (cabozantinib, axitinib, pazopanib, sunitinib, nintedanib, and lenvatinib).However, the instructions for Nintedanib, Sorafenib and Lenvatinib were not mentioned. Capbottinib demonstrated the highest number of reports(1790 cases), also with the strongest association (ROR 95%CI-low = 16.51; PRR = 16.18; IC025 = 3.96) when analyzing the narrow SMQ of TSDs. Dysgeusia, taste disorder, and ageusia were the most commonly reported preferred terms (PTs) in VEGFR-TKI-related TSDs, accounting for more than 90% of the reported cases. Cabozantinib showed the highest number of reports and strongest correlation with ageusia, taste disorder, parosmia, and anosmia. The study found significant association between the reports of TSDs and the use of VEGFR-TKIs, indicating the monitoring of TSD development and appropriate management in clinical is necessary.

A Review of Neoadjuvant Therapy for Localized and Locally Advanced Renal Cell Carcinoma.

The introduction of vascular endothelial growth factor receptor-tyrosine kinases (VEGFR-TKIs) and immune checkpoint inhibitors (IOs) have drastically altered the treatment landscape for kidney cancer, with doublet combination immunotherapy (IO/IO or IO/VEGFR-TKI) now set as the standard front-line treatment for advanced renal cell carcinoma (RCC). However, the roles of VEGFR-TKIs and IOs in the neoadjuvant setting for locoregional/locally advanced RCC remain undefined, where the goals may be primary tumor downsizing/downstaging and potentially eradicating micrometastatic disease. This review will examine VEGFR-TKI monotherapy, IO monotherapy, and VEGFR-TKI/IO combination regimens in a preoperative setting with a focus on the efficacy, toxicity, surgical, and long-term implications.

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.

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. 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. 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. 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). 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.

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.

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.

Histone-Lysine N-Methyltransferase 2D (KMT2D) Impending Therapeutic Target for the Management of Cancer: The Giant Rats Tail.

The histone-lysine N-methyltransferase 2D (KMT2D), tumor suppressor gene which is the major component of histone H3K4 mono-methyltransferase in mammals and has significant role in regulation of a gene which are frequently mutated that lead to many different types of cancers that include non-Hodgkin lymphoma, medulloblastoma, prostate carcinoma, renal carcinoma, bladder carcinoma and lung carcinoma. KMT2D gene epigenetic alterations in histone methylation play a significant role for the initiation and progression of cancers from pre-cancerous lesions, yet its complete function in oncogenesis remains unsolved. KMT2D deficiency - loss are thought of initial mediators of cancer development and cell migration such as B-cell lymphoma, medulloblastoma, melanoma, pancreas and lung cancer. The KMT2D loss has know to activate glycolytic genes that promote aggressive tumor progression. Therefore, the present review serves to underline the update on recent research pertaining to KMT2D gene, that could be a potential therapeutic target in downregulating glycolytic genes such as Pgk1, Ldha, Pgam1 and Gapdh; 2, epidermal growth factor receptor tyrosine kinase (EGFR-TK ) - ERBB2, RTK-RAS signaling, RAS activator genes Rgl1, Rasgrp1, Rasgrf1, Rasgrf 2 and Rapgef5 in suppressing the tumor progression that may represent novel targeted therapy for the management of cancer. This review will facilitate to understand the gene expression that inhibits cancer progression and which could serve as a potential molecular target in understanding cancer pathogenesis.

Atezolizumab, bevacizumab, pemetrexed and platinum for EGFR-mutant NSCLC patients after EGFR TKI failure: A phase II study with immune cell profile analysis.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) remains a significant hurdle forpatients with EGFR-mutated non-small cell lung cancer (NSCLC), particularly those lacking the EGFRT790M. IMpower 150 study demonstrated promising efficacy for a combination of immune-chemotherapy and bevacizumab in patients with EGFR-mutated NSCLC. This open-label, single-arm, phase II trial evaluated the efficacy and immune cell profile of the modified regimen combining atezolizumab, bevacizumab (7.5mg/kg) and chemotherapy in patients with EGFR-mutated NSCLC following TKI failure. The primary endpoint was objective response rate (ORR). The re-biopsy tissue specimens and serial peripheral blood samples were collected to analyse the immune cell profile and tumour microenvironments. 22 EGFR-mutant NSCLC patients participated in this study. The ORR was 42.9%, with a disease control rate (DCR) of 100%. Median progression-free survival (PFS) was 6.3 months. Patients with programmed death-ligand 1 (PD-L1) expression ≥1% exhibited significantly higher ORR (75 vs. 23.1%; p=.032) and longer PFS (14.0 vs. 6.1 months; p=.022) compared with those with PD-L1 expression<1%. Grade≥3 adverse events occurred in 40.9% of patients. Higher peritumour nature killer (NK) cell infiltration and lower peripheral helper T cell counts before treatment were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ myelod-derived suppressor cells (MDSCs) increased, while regulatory T cells decreased. This modified combination regimen may be a promising therapeutic option for EGFR-mutant NSCLC patients with TKI resistance, especially those with PD-L1-positive tumours. Furthermore, immune cell profiling may aid in identifying patients who may benefit from this approach. The combination regimen yielded promising efficacy in NSCLC patients after EGFR-TKI resistance, particularly those with PD-L1-positive tumours. Higher peritumour NK cell and lower peripheral helper T cell were associated with favourable ORR and longer PFS, respectively. After disease progression, the proportion of S100A9+ MDSC increased, but Treg cells decreased.

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.

A novel sensitizer reduces EGFR-TKI resistance by regulating the PI3K/Akt/mTOR pathway and autophagy.

The incidence and mortality of lung cancer are high, and treatment with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the preferred first-line treatment for patients suffering from non-small cell lung cancer (NSCLC) with EGFR mutations. However, EGFR-TKI resistance leads to treatment failure. Yifei-Sanjie pill (YFSJ) is a novel type of Chinese patent medicine for lung cancer. The development of YFSJ has progressed for more than 30 years; however, little is known about the molecular mechanisms associated with the inhibition of drug resistance. In this study, flow cytometry and transcriptome sequencing were used in vitro to explore the anticancer effect of Yifei-Sanjie pill (YFSJ) on EGFR-TKI-resistant cell lines and to identify potential molecular mechanisms associated with the inhibition of drug resistance. We found that in vitro, YFSJ and YFSJ combined with gefitinib significantly reduced the viability of H1975 and H1650cells, which is dose-dependent at 24 and 48h. PI3K, Akt and mTOR were downregulated, while after 24 and 48h of treatment with YFSJ alone and in combination with gefitinib, LC3A and LC3B were up-regulated in both cell lines. YFSJ reduced the viability of EGFR-TKI-resistant cell lines, reducing resistance to gefitinib. This might be caused by a decrease in the PI3K/Akt/mTOR pathway and an increase in autophagy.

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.

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.

Tyrosine Kinase Inhibitors: The Next Chapter in Reducing Treatment Burden for Exudative Retinal Diseases?

Tyrosine kinase inhibitors (TKIs) serve to inhibit the phosphorylation cascade that usually leads to abnormal processes such as vascular leakage and tumorigenesis. Within retinal diseases specifically, dysregulation of the vascular endothelial growth factor receptor tyrosine kinases can lead to age-related macular degeneration and diabetic macular edema. These diseases have a growing prevalence and are leading causes of vision loss. The current standard of care requires repeated administration of anti-vascular endothelial growth factor injections, which poses a significant burden on patients. Novel TKIs provide an opportunity to reduce injection frequency by targeting a broader range of molecules involved in angiogenesis and exudation. This review will cover TKIs in development and how their use of different technologies and targets may enhance visual and anatomic outcomes for patients with exudative retinal disease.

Patients with non‑small cell lung cancer with the exon 21 L858R mutation: From distinct mechanisms to epidermal growth factor receptor tyrosine kinase inhibitor treatments (Review).

The most common oncogenic driver in non-small cell lung cancer (NSCLC) is epidermal growth factor receptor (EGFR) gene mutations, which are more common in Asian (30-50%) than in Caucasian (10-15%) populations. Exon 19 deletion (ex19del) and exon 21 L858R (ex21 L858R) mutations account for ~45 and 40% of all EGFR mutations, respectively. Moreover, EGFR-tyrosine kinase inhibitors (TKIs) may be more effective and improve the quality of life of patients with NSCLC more than chemotherapy regimens. By contrast, patients with the ex21 L858R mutation may have a lower sensitivity and duration of response to EGFR-TKIs as well as a shorter survival compared with those with the ex19del mutation. However, current guidelines classify ex21 L858R and ex19del as the same condition and recommend the same treatment strategy for both. Aiming for precision medicine, the present review introduces and compares different EGFR-TKIs for the ex21 L858R mutation to assess more personalized treatment options for the population with this mutation.

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.

Observational study of the efficacy and safety of first-line osimertinib and later treatments for uncommon epidermal growth factor receptor-activating mutation-positive advanced non-small cell lung cancer.

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is a first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations, including both sensitizing and T790M resistance mutations. Its real-world efficacy against uncommon EGFR mutations remains under-researched. The REIWA study, a multicentric, prospective, observational study conducted in Japan from September 2018 to August 2020, enrolled patients with advanced or recurrent EGFR mutation-positive NSCLC receiving osimertinib. Data on clinical outcomes, safety, disease progression, and subsequent treatments were collected for patients with uncommon EGFR mutations. Of 583 patients receiving osimertinib, 39 (6.7%) had an uncommon EGFR mutation. The present study included 32 of these patients after excluding seven patients with an exon 20 insertion mutation. The overall objective response rate was 53.1% [95% confidence interval (CI): 36.4-69.1], and the disease control rate was 78.1% (95% CI: 61.0-89.3). The median progression-free survival was 9.4months (95% CI: 5.0-20.0), and the median overall survival (OS) was 21.8 (95% CI: 14.4-NA) months. Notably, patients with an exon21 L861Q mutation had a significantly longer OS than those with an exon18 G719X mutation, the respective values being 37.8 and 9.7months (hazard ratio: 0.29; 95% CI: 0.10-0.85; P=0.02). The rate of grade 3 or worse adverse events was 10.3%. Seven out of 32 (21.9%) patients showed progression involving only the central nervous system. Osimertinib demonstrated efficacy and tolerability in the clinical setting in patients with uncommon EGFR mutation-positive NSCLC.

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.

Clinical outcomes of patients with EGFR-mutated NSCLC developing interstitial lung disease during first-line osimertinib therapy: a sub-analysis of the Reiwa study.

Osimertinib-induced interstitial lung disease in untreated EGFR-mutated, advanced non-small cell lung cancer is being reported at a higher rate in Japan than elsewhere. However, data on the interstitial lung disease incidence during first-line osimertinib therapy and the course of lung cancer treatments administered after interstitial lung disease onset in the real-world setting are scarce. The present study reviewed the data from the Reiwa study, a multicentric, observational study examining the efficacy and safety of first-line osimertinib therapy in the clinical setting. Patients with EGFR-mutated non-small cell lung cancer who began osimertinib therapy between September 2018 and August 2020 were enrolled and followed until August 2022. Among 583 patients receiving first-line osimertinib therapy, 75 (12.8%) had interstitial lung disease development, and 18 (3.0%) had at least grade 3 interstitial lung disease. Fifty-nine patients (78%) received some form of treatment following interstitial lung disease onset. An epidermal growth factor receptor-tyrosine kinase inhibitor rechallenge was performed in 31 patients (41%), with 18 (24%) receiving osimertinib again. Interstitial lung disease recurred in five (28%) of these 18 patients, none of 13 patients receiving another type of tyrosine kinase inhibitor, and seven (25%) of 28 patients receiving chemotherapy and/or immune checkpoint inhibitor therapy. The median overall survival after the initial osimertinib therapy was 38.4months and 12.2months for patients with interstitial lung disease grade 1-2 and grade 3-4, respectively (hazard ratio: 0.37; 95% confidence interval: 0.20-0.70; P=0.002). Patients with interstitial lung disease grade 3-4 had poorer survival during the first-line osimertinib therapy. A substantial risk of interstitial lung disease recurrence was associated with post-osimertinib therapy. Trial registration code: UMIN000038683.

The Impact of Bevacizumab and miR200c on EMT and EGFR-TKI Resistance in EGFR-Mutant Lung Cancer Organoids.

Objectives: This research aims to investigate the mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC), particularly focusing on the role of the epithelial-mesenchymal transition (EMT) within the tumor microenvironment (TME). Materials and Methods: We employed an in vitro three-dimensional organoid model that mirrors the physiology of human lung cancer. These organoids consist of lung cancer cells harboring specific EGFR mutations, human mesenchymal stem cells, and human umbilical vein endothelial cells. We analyzed EMT and drug resistance markers, and evaluated the effects of the anti-angiogenic agent Bevacizumab and micro-RNA miR200c. Results: The study identified a significant link between EMT and EGFR-TKI resistance. Notable findings included a decrease in E-cadherin and an increase in Zinc Finger E-Box Binding Homeobox 1 (ZEB1), both of which influenced EMT and resistance to treatment. Bevacizumab showed promise in improving drug resistance and mitigating EMT, suggesting an involvement of the Vascular Endothelial Growth Factor (VEGF) cascade. Transfection with miR200c was associated with improved EMT and drug resistance, further highlighting the role of EMT in TKI resistance. Conclusions: Our research provides significant insights into the EMT-driven EGFR-TKI resistance in NSCLC and offers potential strategies to overcome resistance, including the use of Bevacizumab and miR200c. However, due to the limitations in organoid models in replicating precise human cancer TME and the potential influence of specific EGFR mutations, further in vivo studies and clinical trials are necessary for validation.