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Computational and Mathematical Methods... 2022Lung cancer has been one of the deadliest cancers in the world. Afatinib is an ErbB family irreversible blocker that was authorized by the FDA and EMA in 2013 for the...
Lung cancer has been one of the deadliest cancers in the world. Afatinib is an ErbB family irreversible blocker that was authorized by the FDA and EMA in 2013 for the treatment of advanced EGFR mutation-positive NSCLC. Therefore, we aim to discover the impact of Afatinib on the development of non-small-cell lung cancer (NSCLC) via modulating the Wnt/-catenin signaling pathway. The objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in 22 patients with clinical NSCLC were analyzed as follow-up targets after Afatinib therapy. The differences between the effects of Afatinib treatment and DDP+PEM treatment for conventional chemotherapy were used to measure NSCLC cell proliferation by CCK-8 assay; then those on NSCLC apoptosis were measured by flow cytometry. Patients who received Afatinib had better ORR, DCR, PFS, and OS than those in the conventional chemotherapy group. Meanwhile, CCK-8 assay shows that the number of colony formation of NSCLC cells after Afatinib treatment was less than that in the DDP+PEM group. And NSCLC apoptosis was higher than that in the DDP+PEM group. Phenomenologically, experimental results show that Afatinib can affect the behaviors of NSCLC cells. After treating NSCLC cells with Afatinib, the protein expressions of three serum tumor markers (CEA, CA125, and CY-FRA21-1) were detected by Western blotting, with the findings indicating that the protein expressions in NSCLC cells treated with Afatinib were lower than those of the DDP+PEM group, which indicates that Afatinib treatment can reduce the expressions of tumor markers, and inhibit the development of tumors. Afatinib can affect the progression of NSCLC by modulating the Wnt/-catenin signaling pathway's activity as a new potential therapeutic drug for NSCLC.
Topics: Afatinib; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Wnt Signaling Pathway
PubMed: 35799670
DOI: 10.1155/2022/5213016 -
Frontiers in Immunology 2023Human papilloma virus (HPV)-related cancers are global health challenge. Insufficient comprehension of these cancers has impeded the development of novel therapeutic...
BACKGROUND
Human papilloma virus (HPV)-related cancers are global health challenge. Insufficient comprehension of these cancers has impeded the development of novel therapeutic interventions. Bioinformatics empowered us to investigate these cancers from new entry points.
METHODS
DNA methylation data of cervical squamous cell carcinoma (CESC) and anal squamous cell carcinoma (ASCC) were analyzed to identify the significantly altered pathways. Through analyses integrated with RNA sequencing data of genes in these pathways, genes with strongest correlation to the TNM staging of CESC was identified and their correlations with overall survival in patients were assessed. To find a potential promising drug, correlation analysis of gene expression levels and compound sensitivity was performed. experiments were conducted to validate these findings. We further performed molecular docking experiments to explain our findings.
RESULTS
Significantly altered pathways included immune, HPV infection, oxidative stress, ferroptosis and necroptosis. 10 hub genes in these pathways (PSMD11, RB1, SAE1, TAF15, TFDP1, CORO1C, JOSD1, CDC42, KPNA2 and NUP62) were identified, in which only CDC42 high expression was statistically significantly correlated with overall survival (Hazard Ratio: 1.6, = 0.045). Afatinib was then screened out to be tested. experiments exhibited that the expression level of CDC42 was upregulated in HaCaT/A431 cells transfected with HPV E6 and E7, and the inhibitory effect of afatinib on proliferation was enhanced after transfection. CDC42-GTPase-effector interface-EGFR-afatinib was found to be a stable complex with a highest ZDOCK score of 1264.017.
CONCLUSION
We identified CDC42 as a pivotal gene in the pathophysiology of HPV-related cancers. The upregulation of CDC42 could be a signal for afatinib treatment and the mechanism in which may be an increased affinity of EGFR to afatinib, inferred from a high stability in the quaternary complex of CDC42-GTPase-effector interface-EGFR-afatinib.
Topics: Female; Humans; Afatinib; Carcinoma, Squamous Cell; ErbB Receptors; GTP Phosphohydrolases; Human Papillomavirus Viruses; Molecular Docking Simulation; Papillomavirus Infections; cdc42 GTP-Binding Protein
PubMed: 36936942
DOI: 10.3389/fimmu.2023.1118458 -
Therapeutic Advances in Medical Oncology 2022Although bevacizumab in combination with afatinib or erlotinib is an effective and safe first-line therapy for advanced epidermal growth factor receptor (EGFR)-mutated...
Comparison of afatinib and erlotinib combined with bevacizumab in untreated stage IIIB/IV epidermal growth factor receptor-mutated lung adenocarcinoma patients: a multicenter clinical analysis study.
BACKGROUND
Although bevacizumab in combination with afatinib or erlotinib is an effective and safe first-line therapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), there are very few clinical data comparing afatinib and erlotinib combined with bevacizumab. We performed a retrospective multicenter analysis for the comparison of two combination therapies.
METHODS
Between May 2015 and October 2020, data of 135 stage IIIB/IV EGFR-mutated NSCLC patients receiving first-line afatinib or erlotinib combined with bevacizumab combination therapy in Linkou, Keelung, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals were retrieved and retrospectively analyzed.
RESULTS
In all, 67 patients received afatinib plus bevacizumab, and 68 patients received erlotinib plus bevacizumab. Afatinib combined with bevacizumab had an objective response rate (ORR) of 82.1% and a disease control rate (DCR) of 97.0%, and the ORR and DCR were 83.8 and 95.6%, respectively, in the erlotinib combined with bevacizumab group ( = 0.798 and = 1.000). The median progression-free survival was 20.7 and 20.3 months for the afatinib plus bevacizumab group and the erlotinib plus bevacizumab group, respectively [hazard ratio (HR) = 1.02; 95% confidence interval (CI), 0.891-1.953; = 0.167). The overall survival was 41.9 and 51.0 months for the afatinib plus bevacizumab group and erlotinib plus bevacizumab group, respectively (HR = 1.42; 95% CI, 0.829-2.436; = 0.201). The secondary EGFR-T790M mutation rates after disease progression were 44% in the afatinib plus bevacizumab group and 58.8% in the erlotinib plus bevacizumab group ( = 0.165). Skin toxicity was the most frequent treatment-related adverse event (AE) in both treatment groups. Diarrhea, an AE, occurred significantly more frequently in the afatinib plus bevacizumab group than in the erlotinib plus bevacizumab group ( < 0.05).
CONCLUSION
Afatinib combined with bevacizumab was equally as effective as erlotinib combined with bevacizumab for untreated advanced EGFR-mutated NSCLC. Prospective clinical studies that explore bevacizumab combined with afatinib or erlotinib for advanced EGFR-mutated NSCLC are warranted.
PubMed: 35898964
DOI: 10.1177/17588359221113278 -
Journal of Thoracic Oncology : Official... May 2020
Topics: Afatinib; Data Management; ErbB Receptors; Humans; Lung Neoplasms; Mutation
PubMed: 32340673
DOI: 10.1016/j.jtho.2020.02.013 -
Journal of Cellular Physiology Jun 2021Non-small cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs), such as...
Non-small cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs), such as afatinib. Celastrol, a natural compound with antitumor activity, was reported to induce paraptosis in cancer cells. In this study, intrinsic EGFR-TKI-resistant NSCLC cell lines H23 (EGFR wild-type and KRAS mutation) and H292 (EGFR wild-type and overexpression) were used to test whether celastrol could overcome primary afatinib resistance through paraptosis induction. The synergistic effect of celastrol and afatinib on survival inhibition of the NSCLC cells was evaluated by CCK-8 assay and isobologram analysis. The paraptosis and its modulation were assessed by light and electron microscopy, Western blot analysis, and immunofluorescence. Xenografts models were established to investigate the inhibitory effect of celastrol plus afatinib on the growth of the NSCLC tumors in vivo. Results showed that celastrol acted synergistically with afatinib to suppress the survival of H23 and H292 cells by inducing paraptosis characterized by extensive cytoplasmic vacuolation. This process was independent of apoptosis and not associated with autophagy induction. Afatinib plus celastrol-induced cytoplasmic vacuolation was preceded by endoplasmic reticulum stress and unfolded protein response. Accumulation of intracellular reactive oxygen species and mitochondrial Ca overload may be initiating factors of celastrol/afatinib-induced paraptosis and subsequent cell death. Furthermore, Celastrol and afatinib synergistically suppressed the growth of H23 cell xenograft tumors in vivo. The data indicate that a combination of afatinib and celastrol may be a promising therapeutic strategy to surmount intrinsic afatinib resistance in NSCLC cells.
Topics: Afatinib; Animals; Antineoplastic Combined Chemotherapy Protocols; Calcium; Carcinoma, Non-Small-Cell Lung; Cell Death; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Endoplasmic Reticulum Stress; Humans; Lung Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Pentacyclic Triterpenes; Reactive Oxygen Species; Unfolded Protein Response; Xenograft Model Antitumor Assays; Mice
PubMed: 33230821
DOI: 10.1002/jcp.30172 -
Frontiers in Oncology 2021Resistance to second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), afatinib, is the most significant challenge in the clinical...
INTRODUCTION
Resistance to second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), afatinib, is the most significant challenge in the clinical management of non-small cell lung cancer (NSCLC), and the underlying mechanisms remain unclear.
METHODS
Genomic signatures that may confer afatinib resistance in NSCLC were identified data mining of public databases and integrative bioinformatic analyses. Furthermore, acquired afatinib-resistant lung adenocarcinoma cell lines (HCC827 AR) were established by long-term exposure under afatinib for stepwise escalation. The expression of baculovirus IAP repeat protein 5 (BIRC5) was detected by western blot, and cellular viability of HCC827 AR was determined by CCK8.
RESULTS
Through integrative bioinformatic analyses of public datasets, overexpression of baculovirus IAP repeat protein 5 (BIRC5) was identified in both afatinib-resistant NSCLC cells and tissues, and BIRC5 overexpression was positively correlated with lymph node metastasis as well as pathological stage in NSCLC. Furthermore, NSCLC patients with BIRC5 overexpression showed poor survival outcomes. Immune infiltration analysis suggested that BIRC5 expression was significantly inversely correlated with tumor-infiltrating cell numbers and immune biomarker expression in NSCLC. The functions of genes co-expressed with BIRC5 were mainly enriched in cell cycle mitotic phase transition, double-strand break repair, and negative regulation of the cell cycle process signaling pathway. In addition, overexpression of BIRC5 protein was detected in afatinib-resistant cells by western blot, while BIRC5-expressing cells treated with BIRC5 inhibitor, YM155, were sensitive to afatinib.
CONCLUSIONS
In this study, we showed that overexpression of BIRC5 resulted in resistance to afatinib in NSCLC and BIRC5-specific inhibitors may overcome the resistant phenotype, indicating that dysregulation of the apoptotic cell death pathway may be the key mechanism underlying TKI resistance in the development of NSCLC.
PubMed: 34804966
DOI: 10.3389/fonc.2021.763035 -
Journal of Oncology 2023The aim of this study is to evaluate the efficacy and safety of afatinib in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastasis based on...
AIM
The aim of this study is to evaluate the efficacy and safety of afatinib in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastasis based on meta-analysis.
METHODS
Related literatures were searched in the following databases: EMbase, PubMed, China Knowledge Network (CNKI), Wanfang, Weipu, Google Scholar, the China Biomedical Literature Service System, and other databases. Clinical trials and observational studies that met the requirements were selected for meta-analysis using Revman 5.3. The hazard ratio (HR) was used as an indicator of the impact of afatinib.
RESULTS
A total of 142 related literatures were acquired, but after screening, five literatures were selected for data extraction. The following indices were compared: the progression-free survival (PFS), overall survival (OS), and common adverse reactions (ARs) of grade 3 and above. A total of 448 patients with brain metastases were included and were divided into two groups: the control group (no afatinib treatment, with chemotherapy alone and the first-generation EGFR-TKIs) and the afatinib group. The results showed that afatinib could improve PFS (HR: 0.58, 95% CI: 0.39-0.85, < 0.05) and ORR (OR = 2.86, 95% CI: 1.45-2.57, < 0.05), but had no benefit on OS (HR: 1.13, 95% CI: 0.15-8.75, > 0.05) and DCR (OR = 2.87, 95% CI: 0.97-8.48, > 0.05). For the safety of afatinib, the incidence of grade-3-and-above ARs was low (HR: 0.01, 95% CI: 0.00-0.02, < 0.05).
CONCLUSION
Afatinib improves the survival of NSCLC patients with brain metastases and shows satisfactory safety.
PubMed: 37228701
DOI: 10.1155/2023/5493725 -
Targeting the EGFR pathway: An alternative strategy for the treatment of tuberous sclerosis complex?Neuropathology and Applied Neurobiology Apr 2024Tuberous sclerosis complex (TSC) is caused by variants in TSC1/TSC2, leading to constitutive activation of the mammalian target of rapamycin (mTOR) complex 1. Therapy...
INTRODUCTION
Tuberous sclerosis complex (TSC) is caused by variants in TSC1/TSC2, leading to constitutive activation of the mammalian target of rapamycin (mTOR) complex 1. Therapy with everolimus has been approved for TSC, but variations in success are frequent. Recently, caudal late interneuron progenitor (CLIP) cells were identified as a common origin of the TSC brain pathologies such as subependymal giant cell astrocytomas (SEGA) and cortical tubers (CT). Further, targeting the epidermal growth factor receptor (EGFR) with afatinib, which is expressed in CLIP cells, reduces cell growth in cerebral TSC organoids. However, investigation of clinical patient-derived data is lacking.
AIMS
Observation of EGFR expression in SEGA, CT and focal cortical dysplasia (FCD) 2B human brain specimen and investigation of whether its inhibition could be a potential therapeutic intervention for these patients.
METHODS
Brain specimens of 23 SEGAs, 6 CTs, 20 FCD2Bs and 17 controls were analysed via immunohistochemistry to characterise EGFR expression, cell proliferation (via Mib1) and mTOR signalling. In a cell-based assay using primary patient-derived cells (CT n = 1, FCD2B n = 1 and SEGA n = 4), the effects of afatinib and everolimus on cell proliferation and cell viability were observed.
RESULTS
EGFR overexpression was observed in histological sections of SEGA, CT and FCD2B patients. Both everolimus and afatinib decreased the proliferation and viability in primary SEGA, tuber and FCD2B cells.
CONCLUSION
Our study demonstrates that EGFR suppression might be an effective alternative treatment option for SEGAs and tubers, as well as other mTOR-associated malformations of cortical development, including FCD2B.
Topics: Humans; Everolimus; Tuberous Sclerosis; Afatinib; TOR Serine-Threonine Kinases; Astrocytoma; Mechanistic Target of Rapamycin Complex 1; ErbB Receptors
PubMed: 38562027
DOI: 10.1111/nan.12974 -
BMC Cancer Nov 2022The optimal duration of anti-PD-1 for cancer therapy has not been tested, especially when using combination therapy. Epidermal growth factor receptor (EGFR) pathway...
OBJECTIVES
The optimal duration of anti-PD-1 for cancer therapy has not been tested, especially when using combination therapy. Epidermal growth factor receptor (EGFR) pathway blocker was the top compound that enhanced T-cell killing of tumor cells in a high-throughput immune-oncology screen, possibly by stimulate the antigen presentation machinery and other mechanisms. We explored the effect of combination of EGFR inhibition with a short course of anti-PD-1 therapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC).
METHOD
We analyzed the effect of a short course of anti-PD-1 with continuous afatinib on the survival of a real-world cohort of R/M HNSCC patients. Patient characteristics, treatments, efficacies, and toxicities were reviewed and recorded for analysis.
RESULTS
From November 2016 to May 2018, 51 consecutive patients received pembrolizumab and afatinib. The cutoff date was June 30, 2022. The most common toxicities (all grades) were diarrhea (62.7%), skin rash (43.1%), mucositis (31.4%), and paronychia (23.5%). The objective response rate was 54.9% (95% confidence interval [CI] 40.3-68.9%). Median progression-free survival was 5.9 months (95% CI: 4.4-7.6 months), and the median overall survival was 10.5 months (95% CI: 6.8-16.5 months). The 12-month, 24-month, 36-month, and 48-month survival rate was 47.0%, 22.5%, 17.7%, and 12.6% respectively.
CONCLUSIONS
This retrospective study showed that short course pembrolizumab with afatinib therapy has acceptable efficacy in R/M HNSCC patients. The durable response and long-term survival rates were similar to prospective clinical trials. Short course anti-PD-1 therapy, especially in combination with EGFR blocker, is worth for further prospective study.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Afatinib; Retrospective Studies; Data Analysis; Prospective Studies; Head and Neck Neoplasms; Carcinoma; ErbB Receptors
PubMed: 36443704
DOI: 10.1186/s12885-022-10343-7 -
Journal of Neuro-oncology Dec 2021Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene,...
BACKGROUND
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM.
METHODS
This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment.
RESULTS
Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone.
CONCLUSIONS
This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection.
TRIAL REGISTRATION
NCT00977431 (first posted September 15, 2009).
Topics: Adult; Afatinib; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Dacarbazine; Glioblastoma; Humans; Temozolomide; Treatment Outcome
PubMed: 34787778
DOI: 10.1007/s11060-021-03877-6