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BACKGROUND: Ongoing studies are evaluating the efficacy and toxicity profiles of combining epidermal growth factor receptor inhibitors (EGFR-TKIs) with antiangiogenic agents in non-small cell lung cancer (NSCLC). However, the complete toxicity profiles remain elusive. RESEARCH DESIGN AND METHODS: This study conducted an extensive pharmacovigilance analysis utilizing the FDA Adverse Event Reporting System database. The analysis focused on identifying and characterizing adverse events (AEs) associated with the concurrent use of EGFR-TKIs and antiangiogenic inhibitors in patients with NSCLC. RESULTS: The study identified significant occurrences of AEs linked to the combination therapy, particularly impacting general disorders, skin and subcutaneous tissue conditions, and vascular disorders. Frequently reported AEs included rash, diarrhea, fatigue, nausea, decreased appetite, and anemia. Notably, the combination of EGFR-TKIs with antiangiogenic inhibitors resulted in an increased incidence of AEs across multiple organ systems compared to EGFR-TKIs alone, with some adverse effects, such as anemia, arrhythmia, and ulcerative keratitis, persisting beyond one year in a subset of patients. CONCLUSIONS: The combination of EGFR-TKIs and antiangiogenic inhibitors in NSCLC treatment presents a distinct and substantial AE profile, often with delayed onset. This finding underscores the necessity for rigorous and ongoing monitoring protocols to mitigate potential long-term adverse effects.
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PURPOSE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer. METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023. RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87). CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.
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Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Clorhidrato de Erlotinib , Gefitinib , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Anciano , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Receptores ErbB/antagonistas & inhibidores , Gefitinib/administración & dosificación , Gefitinib/uso terapéutico , Gefitinib/farmacología , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/farmacología , Clorhidrato de Erlotinib/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Afatinib/administración & dosificación , Afatinib/uso terapéutico , Afatinib/farmacología , Estudios de Cohortes , Anciano de 80 o más Años , AdultoRESUMEN
The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFRdel19/T790M/C797S). Compound b demonstrated slightly improved inhibition activity against PC-9del19/T790M/C797S (IC50 = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.
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This study investigates the repurposing potential of non-nucleosidic reverse transcriptase inhibitors (NNRTIs), specifically Rilpivirine and Etravirine, as L858R/T790M tyrosine kinase inhibitors for addressing acquired resistance in non-small cell lung cancer (NSCLC). Using in silico molecular docking, Rilpivirine demonstrated a docking score of -7.534 kcal/mol, comparable to established epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) like Osimertinib and WZ4002. Molecular dynamics (MD) simulations over 200 ns revealed the stability of the Rilpivirine-EGFR complex, with RMSD values ranging from 2.5 to 3.5 Å. The in vitro antiproliferative assays showed that Rilpivirine had an IC50 value of 2.3 µM against H1975 cells, while WZ4002 had an IC50 of 0.291 µM, indicating moderate efficacy. Enzymatic assays revealed that Rilpivirine inhibited the double mutant epidermal growth factor receptor tyrosine kinase (EGFR TK) with an IC50 value of 54.22 nM and spared the wild-type EGFR TK with an IC50 of 22.52 nM. These findings suggest Rilpivirine's potential as a therapeutic agent for NSCLC with EGFR L858R/T790M mutations.
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Molecular targeted therapy resistance remains a major challenge in treating lung adenocarcinoma (LUAD). The resistance of Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitor) plays a dominant role in molecular targeted therapy. Our previous research demonstrated the role of MALAT-1 (Metastasis-associated lung adenocarcinoma transcript 1) in the formation of Erlotinib-resistant LUAD cells. This study aims to uncover the mechanism of MALAT-1 overexpression in Erlotinib-resistant LUAD cells. The RT2 LncRNA PCR array system was used to explore MALAT-1 regulation in Erlotinib-resistant LUAD cells through patient serum analysis. Dual luciferase reporter experiments confirmed the binding between MALAT-1 and miR-125, leading to regulation of miR-125 expression. Functional assays were performed to elucidate the impact of MALAT1 on modulating drug resistance, growth, and Epithelial-mesenchymal transition (EMT, Epithelial-mesenchymal transition) in both parental and Erlotinib-resistant LUAD cells. The investigation unveiled the mechanism underlying the competing endogenous RNA (ceRNA, competing endogenouse RNA) pathway. MALAT1 exerted its regulatory effect on miR-125 as a competing endogenous RNA (ceRNA). Moreover, MALAT1 played a role in modulating the sensitivity of LUAD cells to Erlotinib. Rab25 was identified as the direct target of miR-125 and mediated the functional effects of MALAT1 in Erlotinib-resistant LUAD cells. In conclusion, our study reveals overexpress MALAT-1 cause the drug resistance of EGFR-TKIs in non-small cell lung cancer (NSCLC) through the MALAT-1/miR-125/Rab25 axis. These findings present a potential novel therapeutic target and perspective for the treatment of LUAD.
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PURPOSE: The most appropriate time of primary tumor radiotherapy in non-small cell lung cancer(NSCLC) with EGFR-TKIs remains unclear. The aim of this study was to investigate the effect of the time factor of primary tumor radiotherapy on long-term overall survival(OS)and provide a theoretical basis for further clinical research. PATIENTS AND METHODS: In total, 238 patients with EGFR-TKIs and OS ≥ 12 months were statistically analysed. Patients were grouped: the D group without primary tumor radiotherapy and the R group with it.The R group were divided into three groups according to the interval between the start of EGFR-TKIs and the start of primary tumor radiotherapy: R0 - 30(<30 days), R30 - PD(≥ 30 days and disease stable), and RPD(radiotherapy after disease progression). The Kaplan-Meier method and log-rank test were used for survival analyses. Exploratory landmark analyses were investigated. RESULTS: The OS rates at 1, 2, 3, 5 years for the R group and D group were 96.8%, 62.9%, 38.3%, 17.1%, and 95.6%, 37.7%, 21.8%, 2.9%, respectively; the corresponding MST was 29 months(95% CI: 24.3-33.7) for the R group and 22 months(95% CI: 20.4-23.6) for the D group (χ2 = 13.480, p<0.001). Multivariate analysis revealed that primary tumor radiotherapy was independent predictors of prolonged OS.Among the four groups, The R30 - PD appeared to have the best OS (D, χ2 = 19.307, p<0.001;R0 - 30, χ2 = 11.687, p = 0.01; RPD, χ2 = 4.086, p = 0.043). Landmark analyses(22 months) showed the R30 - PD group had a significant long-term OS.The incidence of radiation pneumonitis ≥ grade 2 was17.3%(n = 19)and radiation esophagitis ≥ grade 2 was observed in 32 patients(29.1%). CONCLUSIONS: Our results showed that primary tumour radiotherapy may prolong long-term OS with acceptable toxicities. Appropriate delay(R30 - PD)of primary tumour radiotherapy may be the best choice.Premature radiotherapy(R0 - 30) and radiotherapy after disease progression (RPD)may not be reasonable for long-term OS.
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Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Masculino , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Receptores ErbB/antagonistas & inhibidores , Anciano , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano de 80 o más Años , Estimación de Kaplan-Meier , Estudios Retrospectivos , Tasa de Supervivencia , Tiempo de TratamientoRESUMEN
Non-small cell lung cancer (NSCLC) poses a global health threat, and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib, afatinib, and osimertinib have achieved significant success in clinical treatment. However, the emergence of resistance limits the long-term efficacy of these treatments, necessitating urgent exploration of novel EGFR-TKIs. This review provides an in-depth summary and exploration of the resistance mechanisms associated with EGFR-TKIs, with a specific focus on representative drugs like gefitinib, afatinib, and osimertinib. Additionally, the review introduces a therapeutic strategy involving the combination of Chinese herbal medicines (CHMs) and chemotherapy drugs, highlighting the potential role of CHMs in overcoming NSCLC resistance. Through systematic analysis, we elucidate the primary resistance mechanisms of EGFR-TKIs in NSCLC treatment, emphasizing CHMs as potential treatment medicines and providing a fresh perspective for the development of next-generation EGFR-TKIs. This comprehensive review aims to guide the application of CHMs in combination therapy for NSCLC management, fostering the development of more effective and comprehensive treatment modalities to ultimately enhance patient outcomes.
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Carcinoma de Pulmón de Células no Pequeñas , Medicamentos Herbarios Chinos , Receptores ErbB , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
Lung cancer is the leading cause of cancer-related death worldwide, especially non-small cell lung cancer. Early diagnosis and better treatment choices have already provided a more promising prognosis for cancer patients. In targeted therapy, antagonists target specific genes supporting cancer growth, proliferation and metastasis. With the incorporation of targeted therapies in routine cancer therapy, it is imperative that the array of toxicities associated with these agents must be well-recognized and managed, especially since these toxicities are distinct from those seen with conventional cytotoxic agents. Drug-related nephrotoxicity has attracted attention when initiating cancer therapy. Our review aims to summarize the adverse renal effects caused by targeted therapy during lung cancer treatment, mainly focusing on EGFR and ALK tyrosine kinase inhibitors. Also, we discuss the possible mechanism of the side effect and provide managements to help improve the renal function in clinical practice.
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Antineoplásicos , Neoplasias Pulmonares , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Receptores ErbB/antagonistas & inhibidores , Animales , Enfermedades Renales/inducido químicamente , Riñón/efectos de los fármacos , Riñón/patología , Riñón/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológicoRESUMEN
BACKGROUND: Sodium voltage-gated channel beta subunit 4 (SCN4B) plays a suppressive role in various tumors. However, the role of SCN4B in non-small cell lung cancer (NSCLC) is not yet clear. This study aims to investigate the expression of SCN4B in NSCLC patients and its correlation with prognosis. METHODS: Firstly, the expression of SCN4B in non-small cell lung cancer (NSCLC) was analyzed using The Cancer Genome Atlas (TCGA) database. Then, differential expression genes (DEGs) were identified using R software. Next, DEG enrichment pathways were analyzed using the R package clusterProfiler. Protein-protein interaction networks were revealed through STRING analysis. A heatmap showed significant differential expression of SCN4B. Further analysis included examining SCN4B expression in a pan-cancer context and its correlation with 24 types of immune cells in NSCLC. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR), Western Blot, immunohistochemistry, and clinical data were used to validate SCN4B expression and prognostic value in NSCLC patients. RESULTS: SCN4B mRNA expression in non-small cell lung cancer tissues was significantly lower than in adjacent normal tissues (p < 0.001). Clinical correlation analysis confirmed its association with clinical pathology. Gene set enrichment analysis (GSEA) and tumor immune-related analyses indicated that SCN4B is involved in NSCLC-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and participates in immune infiltration. qRT-PCR, Western Blot, and immunohistochemistry also confirmed that SCN4B is downregulated in NSCLC patients and is associated with poor prognosis. CONCLUSION: SCN4B is downregulated in tumor tissues of NSCLC patients and is associated with a poor prognosis.
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INTRODUCTION: Icotinib and almonertinib are efficacious for non-small cell lung cancer (NSCLC) factor patients with epidermal growth receptor (EGFR)-mutation. Patients who previously used EGFR tyrosine kinase inhibitor (EGFR TKI) may switch to another one due to the adverse events. CASE PRESENTATION: Here, we report a case of a 73-year-old male patient with advanced lung adenocarcinoma in which an EGFR (exon 21 L858R substitution) was found. Icotinib (125mg three times daily) was administered initially. He achieved partial response two months later but developed acute interstitial lung disease (grade 2) with dry cough and chest tightness five months later. Icotinib was discontinued, and treatment with methylprednisolone improved the interstitial lung disease. Chemotherapy with pemetrexed, carboplatin, and bevacizumab was initiated as subsequent therapy. Considering the effectiveness of EGFR-TKIs, we decided cautiously to rechallenge the third-generation TKI almonertinib administration. The patient successfully received almonertinib for almost one year without the recurrence of interstitial lung disease and tumor progression. ILD was an infrequent but often life-threatening reaction associated with icotinib. CONCLUSION: This is the first reported case of successful switching from icotinib to another EGFR TKI because of interstitial lung disease associated with icotinib, suggesting that EGFR-TKIs rechallenge because of adverse events rather than progression might provide a significant benefit in patients with EGFR driver positive NSCLC.
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There is an urgent need to fully understand the biology of third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), particularly osimertinib, and to develop mechanism-driven strategies to manage their acquired resistance. Transient receptor potential melastatin-2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR-TKIs and acquired resistance to EGFR-TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR-TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy-optimized TRPM2 inhibitors.
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BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are key drivers in a significant portion of non-small-cell lung cancer (NSCLC) patients. While third-generation EGFR-tyrosine kinase inhibitors (TKIs) such as osimertinib have demonstrated efficacy, the management of patients who continue to experience disease progression during treatment remains challenging. The emergence of drug resistance, including the development of secondary mutations, necessitates exploration of alternative treatment strategies. This study aims to evaluate and observe the efficacy and safety of almonertinib combined with anlotinib in patients after cancer progression during third-generation EGFR-TKI therapy. METHODS: In this retrospective analysis, we included EGFR-mutated NSCLC patients who were resistant to third-generation EGFR-TKIs. All patients were treated with almonertinib combined with anlotinib. The clinical characteristics, treatment history, clinical benefits, and adverse events of these patients were retrospectively collected. RESULTS: A total of 16 eligible patients were included in the analysis. The results revealed that combination therapy with almonertinib and anlotinib was effective in this patient cohort. The overall response rate was 25% and the disease control rate was 93.75%. The 6 and 12 months of PFS rates were 92.9% (95% confidence interval [CI] 80.3%, 100.0%) and 84.4% (95% CI 66.6%, 100.0%), respectively. Moreover, this combination therapy was generally well-tolerated, with manageable adverse events. CONCLUSION: Our retrospective analysis suggests that almonertinib and anlotinib combination therapy may represent a viable option for EGFR-mutated NSCLC patients who have progressed on third-generation EGFR-TKIs, especially for those with posterior lines and no standard treatment options. Further investigation and larger clinical trials are warranted to validate these observations and refine treatment guidelines.
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Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Quinolinas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Masculino , Estudios Retrospectivos , Femenino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Indoles/uso terapéutico , Indoles/administración & dosificación , Anciano , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores ErbB/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Progresión de la Enfermedad , AdultoRESUMEN
Objective: To investigate the risk factors associated with cardiotoxicity in patients with non-small cell lung cancer (NSCLC) treated with osimertinib. Methods: A total of 268 patients with NSCLC treated with osimertinib in our hospital from June 2019 to December 2023 were selected to observe the occurrence of cardiotoxicity and were divided into cardiotoxicity group and non-cardiotoxicity group. The differences in age, gender, body mass index (BMI), smoking, alcohol consumption, tumor stage, hypertension, diabetes, hyperlipidemia, chemotherapy, radiotherapy, antiangiogenic drugs, and osimertinib treatment time were recorded and analyzed. Logistic regression was used to analyze the risk factors for cardiotoxicity in patients with non-small cell lung cancer caused by osimertinib treatment. Results: Among the 268 patients with NSCLC treated with osimertinib, 58 patients developed cardiotoxicity, and the incidence of cardiotoxicity was 21.64%. There were statistically significant differences between the cardiotoxicity group and the non-cardiotoxicity group in terms of smoking history, hyperlipidemia history, combined chemotherapy, and combined radiotherapy (P < 0.05). Further analysis showed that patients with a smoking history were at increased risk of cardiotoxicity compared with non-smoking patients (OR = 2.569, 95% CI = 1.398-6.523). Patients with hyperlipidemia were at increased risk of cardiotoxicity compared with those without hyperlipidemia (OR = 3.412, 95% CI = 2.539-7.628). Patients with chemotherapy were at increased risk of cardiotoxicity compared with those without combination chemotherapy (OR = 2.018, 95% CI = 1.426-4.517). Patients undergoing radiotherapy to the left chest were at increased risk of cardiotoxicity compared with those without combined radiotherapy (OR = 1.629, 95% CI = 1.273-4.206). Conclusion: The incidence of cardiotoxicity in patients with NSCLC is high due to osimertinib treatment. A history of smoking, hyperlipidemia, combination chemotherapy, and radiotherapy to the left chest are independent risk factors for cardiotoxicity in patients with NSCLC treated with osimertinib.
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Purpose: Activating mutations in epidermal growth factor receptor (EGFR) have been identified as key predictive biomarkers for the customized treatment with EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), aiding in improving patient response rates and survival. However, resistance challenges the efficacy of these treatments, with limited understanding of post-resistance therapeutic strategies. A deep understanding of the biology and resistance mechanisms of EGFR-mutant NSCLC is crucial for developing new treatment approaches. This study, through bibliometric analysis, summarizes the trends in research on resistance to EGFR-TKIs. Methods: Research papers on NSCLC with EGFR inhibitor resistance were collected from the Web of Science Core Collection (WoSCC). The analysis utilized bibliometric tools like CiteSpace, VOSviewer, and other platforms for comprehensive analysis and visualization of the outcomes. Results: The WoSCC database contains a total of 5866 documents on resistance to EGFR-TKIs treatment, including 4727 articles (93.48%) and 1139 reviews (6.52%), spanning 81 countries and regions, 4792 institutions, with the involvement of 23,594 authors. Since 2016, there has been a significant increase in publications in this field. China has the highest publication output, while the United States has the highest citation count for papers. Harvard University leads in terms of the number of publications. Among the top ten journals with the highest output, Clinical Cancer Research has the highest impact factor at 11.5, with 90% of the journals classified in Q1 or Q2. Rafael Rosell is one of the most influential authors in this field, ranking second in publication volume and fourth in citation count. Research on EGFR-TKIs resistance mainly focuses on genetic testing, resistance mechanisms, and post-resistance treatment strategies. Conclusion: This study provides researchers with a reliable basis and guidance for finding authoritative references, understanding research trends, and exploring potential directions.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bibliometría , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) represents a primary cause of treatment failure in non-small cell lung cancer (NSCLC) patients. Chemokine (C-C motif) ligand 2 (CCL2) is recently found to play a pivotal role in determining anti-cancer treatment response. However, the role and mechanism of CCL2 in the development of EGFR-TKIs resistance have not been fully elucidated. In the present study, we focus on the function of CCL2 in the development of acquired resistance to EGFR-TKIs in NSCLC cells. Our results show that CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells and that CCL2 overexpression significantly diminishes sensitivity to EGFR-TKIs. Conversely, CCL2 suppression by CCL2 synthesis inhibitor, bindarit, or CCL2 knockdown can reverse this resistance. CCL2 upregulation can also lead to enhanced migration and increased expressions of epithelial-mesenchymal transition (EMT) markers in EGFR-TKI-resistant NSCLC cells, which could also be rescued by CCL2 knockdown or inhibition. Furthermore, our findings suggest that CCL2-dependent EGFR-TKIs resistance involves the AKT-EMT signaling pathway; inhibition of this pathway effectively attenuates CCL2-induced cell migration and EMT marker expression. In summary, CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC. These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC.
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BACKGROUND: The treatment of non-small cell lung cancer (NSCLC) patients can be complicated by the presence of the EGFR-T790M mutation. Although primary or secondary EGFR-T790M mutations have been extensively studied worldwide, there are few reports on the clinicopathological characteristics and physiological mechanisms of lung adenocarcinoma (LUAD) with only the EGFR-T790M primary mutation. METHODS: The clinical data of all LUAD patients with only the EGFR-T790M primary mutation were collected. Immunohistochemical staining was performed on cell cycle-related proteins, targeted therapy indicators, and prognosis-related proteins in the specimens obtained from puncture biopsies or surgeries. OBJECTIVES: The aim of this study is to analyze the clinicopathological features and possible physiological mechanisms of only the EGFR-T790M primary mutation in LUAD, and to offer recommendations for clinical management. RESULTS: Two patients who have only the T790M de novo mutation were both female (2/12,928, 0.02%). ß-catenin and Cyclin D1 were both highly expressed. In case 1, IHC results showed a positive Ki67 and mutant P53 and there was a significant increase in serum CYFRA 21-1. Third-generation of EGFR TKIs resulted in a partial response (PR) time of less than 8 months in case 1. In case 2, the patient underwent surgical resection and adjuvant chemotherapy, resulting in a progression-free survival (PFS) time of 25 months. CONCLUSION: The results suggest that abnormal activation of the Wnt signaling pathway may be specifically associated with the EGFR-T790M primary mutation in LUAD. Furthermore, it has been observed that patients with significant Ki67, mutant P53, and CYFRA 21-1 expression tend to have a poor prognosis.