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Journal of Cranio-maxillo-facial... Mar 2018Melanoma-associated antigen A (MAGE-A) proteins are members of the cancer/testis antigens (CTA), and the expression of these proteins is almost exclusively limited to...
Melanoma-associated antigen A (MAGE-A) proteins are members of the cancer/testis antigens (CTA), and the expression of these proteins is almost exclusively limited to malignant cells, making them an attractive treatment target. MAGE-A expression is correlated with poor overall survival in several cancers, including head and neck squamous cell carcinoma (HNSCC). Among others, MAGE-A11 was found to be associated with resistance to different antineoplastic and targeted compounds, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We searched The Cancer Genome Atlas (TCGA) database with a focus on MAGE-A and found that MAGE-A overexpression is a common event in HNSCC (27.5%). Furthermore, MAGE-A overexpression was correlated with significantly reduced overall survival (35.45 months vs. 64.78 months, P = 0.0173). In particular, MAGE-A11 overexpression was found in 9% of specimens. We then examined MAGE-A11 expression, the efficacy of EGFR and the EGFR mutational status and the effects of the pan-HER (human EGFR) TKIs erlotinib and afatinib in HNSCC cell lines. Next, we used a model of stable MAGE-A11 overexpression to demonstrate that MAGE-A11 impaired the efficacy of erlotinib and afatinib. In summary, our study provides evidence that MAGE-A11 contributes to erlotinib and afatinib resistance in head and neck cancer cell lines.
Topics: Afatinib; Antigens, Neoplasm; Antineoplastic Agents; Erlotinib Hydrochloride; Humans; Neoplasm Proteins; Squamous Cell Carcinoma of Head and Neck; Treatment Outcome; Tumor Cells, Cultured
PubMed: 29311018
DOI: 10.1016/j.jcms.2017.12.014 -
Ophthalmic Plastic and Reconstructive... 2019Epidermal growth factor receptor tyrosine kinase inhibitor therapy has been increasingly employed in the treatment of a variety of tumors. The authors report the rarely...
Epidermal growth factor receptor tyrosine kinase inhibitor therapy has been increasingly employed in the treatment of a variety of tumors. The authors report the rarely documented side effect of trichiasis with the use of Afatinib in a patient with spinal chordoma and review-related literature. A 67-year-old lady was referred to the oculoplastic service with a 3-month history of ocular irritation and pain associated with blurred vision. She has a 4-year history of spinal chordoma treated with daily Afatinib 50 mg over the past 6 months. Clinical examination revealed trichomegaly and trichiasis affecting all 4 eyelids associated with blepharitis, conjunctival, and corneal abrasion on fluorescein staining. Hypertrichosis of the eyebrow bilaterally was also present. Afatinib and other epidermal growth factor receptor tyrosine kinase inhibitor-associated changes to eyelash and eyebrow hair is a result of epidermal growth factor receptor pathway activation in keratinocytes results in remodeling of the hair follicle. This results in the variation in the severity of clinical presentation of trichiasis.
Topics: Afatinib; Aged; Chondroma; Eyelids; Female; Humans; Protein Kinase Inhibitors; Slit Lamp Microscopy; Spinal Neoplasms; Trichiasis
PubMed: 30531213
DOI: 10.1097/IOP.0000000000001277 -
Acta Oncologica (Stockholm, Sweden) Dec 2023Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are a standard of care treatment options in non-small cell lung cancer (NSCLC). The present...
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are a standard of care treatment options in non-small cell lung cancer (NSCLC). The present study investigated real-world EGFR TKI use and patient outcomes in NSCLC.
MATERIAL AND METHODS
We collected all the patients who had reimbursement for EGFR TKIs in Finland 2011-2020 and had data available at Finnish Cancer Registry. Survival and time-on-treatment (ToT) were analyzed from the first EGFR TKI purchase and patients were stratified according to the TKIs.
RESULTS
Whole patient cohort consisted of 1498 individuals who were treated with erlotinib ( = 998), afatinib ( = 258), or gefitinib ( = 238). In the mutant cohort (all gefitinib users and afatinib users with non-squamous histology; = 466), survival was comparable to registrational trials while patients treated with afatinib had improved survival (HR 0.67 CI 95% 0.53-0.85) and longer ToT (13.9 vs 11.9 months, NS) compared to those treated with gefitinib. Females treated with afatinib had improved survival (HR 0.61 CI 95% 0.44-0.83) and longer ToT (15.1 vs 12.5 months, NS) compared to gefitinib while similar was not observed in males. Later line osimertinib treatment was applied for 78 patients. Approximately 20% of the individuals treated with previous gefitinib or afatinib had later line osimertinib treatment. Efficacy analysis of osimertinib treated showed similar ToT and survival regardless of the first line EGFR TKI.
CONCLUSIONS
mutants treated with afatinib have improved outcomes compared to gefitinib while later-line osimertinib was applied only for around 20% of the individuals. The study further highlights the good real-world performance of EGFR TKIs and sheds light on therapy sequencing.
Topics: Male; Female; Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Gefitinib; Tyrosine Kinase Inhibitors; Lung Neoplasms; Cohort Studies; Protein Kinase Inhibitors; Treatment Outcome; ErbB Receptors; Mutation
PubMed: 37934101
DOI: 10.1080/0284186X.2023.2274481 -
Oral Oncology Aug 2022To identify the most effective PI3K and EGFR inhibitors in HPV-positive head and neck squamous cell carcinoma (HNSCC) and investigate the efficacy of a combination of an...
OBJECTIVES
To identify the most effective PI3K and EGFR inhibitors in HPV-positive head and neck squamous cell carcinoma (HNSCC) and investigate the efficacy of a combination of an ErbB family kinase inhibitor and a PI3K inhibitor to inhibit cell proliferation of HPV-positive HNSCC.
MATERIALS AND METHOD
HPV-positive HNSCC cell lines were treated with the FDA approved ErbB kinase inhibitor, Afatinib or FDA-approved PI3K inhibitor, Copanlisib, alone or in combination, and phosphorylation and total protein levels of cells were assessed by Western blot analysis.Cell proliferation and apoptosis were examined by MTS assay, flow cytometry, and Western blots, respectively.
RESULTS
Copanlisib more effectively inhibited cell proliferation in comparison to other PI3K inhibitors tested. HPV-positive HNSCC cells differentially responded to cisplatin, Afatinib, or Copanlisib. The combination of Afatinib and Copanlisib more effectively suppressed cell proliferation and induced apoptosis compared to either treatment alone. Mechanistically, the combination of Afatinib and Copanlisib completely blocked phosphorylation of EGFR, HER2, HER3, and Akt as well as significantly decreased the HPV E7 expression compared to either treatment alone.
CONCLUSION
Afatinib and Copanlisib more effectively suppress cell proliferation and survival of HPV-positive HNSCC in comparison to either treatment alone.
Topics: Afatinib; Antineoplastic Agents; Cell Line, Tumor; ErbB Receptors; Head and Neck Neoplasms; Humans; Papillomavirus Infections; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Squamous Cell Carcinoma of Head and Neck
PubMed: 35667295
DOI: 10.1016/j.oraloncology.2022.105939 -
Biomedicine & Pharmacotherapy =... Feb 2021Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients...
Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutation. However, some lung cancer patients fail to respond and eventually develop drug resistance. Therefore, new therapeutic strategies are needed to improve the outcomes for substantial clinical benefit. Here we aimed to explore the combination of vinorelbine with the second EGFR-TKI afatinib in NSCLC cells with or without EGFR mutation. The three cells of H1975, HCC827, and H460 were assessed for the combination of vinorelbine and afatinib. Vinorelbine combined with afatinib synergistically inhibited the three lung cancer cells growth without aggravating adverse effect on the normal lung cells. The combination of low doses of vinorelbine and afatinib suppressed the cancer cell proliferation by cell colony formation assay and significantly induced cell apoptosis. The anti-apoptotic proteins Bcl-xL and Bcl-2 showed significant reduction after the drug combination treatment, while the pro-apoptotic protein Bax as well as apoptosis indicators cytochrome C and cleaved PARP were observed a notable increasing. EGFR downstream pathways including AKT, ERK, JNK, and p38 were highly active and p53 was inactive in the three lung cancer cells, favoring tumor growth. The low doses of vinorelbine plus afatinib blocked the phosphorylation of AKT, ERK, JNK, and p38, but restored the expression of p53. Our findings suggested that the combination of vinorelbine and afatinib could be recommended as a therapeutic regimen for treatment of NSCLC with or without EGFR mutation.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; ErbB Receptors; Humans; Lung Neoplasms; Signal Transduction; Tumor Suppressor Protein p53; Vinorelbine
PubMed: 33360044
DOI: 10.1016/j.biopha.2020.111144 -
Thoracic Cancer Nov 2021Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved the prognosis of mutant lung cancer; however, the clinical application value of...
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved the prognosis of mutant lung cancer; however, the clinical application value of TKIs for nonclassical EGFR mutation is unclear, especially for patients with rare uncommon mutations.
METHODS
A retrospective study based on electronic medical records was conducted to collect data on the effectiveness of afatinib in patients with stage IIIB/IV lung adenocarcinoma (LUAD) bearing uncommon mutations between January 2017 and January 2021.
RESULTS
Forty-two patients with uncommon mutations treated with afatinib were enrolled. The objective response rate (ORR) was 50.0% (10 of 20 patients). The median time to treatment failure (TTF) was 11.7 months (95% confidence interval = 8.5-18.3 months). Of the 42 patients, the median TTF was 15.0, 11.7, and 16.6 months in patients with Gly719Xaa (G719X), Ser768Ile (S768I), and Leu861Gln (L861Q) mutations, respectively. In patients with the rare uncommon mutation, the median TTF was 10.0 months, and the ORR was 50.0%. Afatinib demonstrated clinical activity across a set type of specific rare uncommon mutations, including EGFR L747P, A767_V769dup, and L833V/H835L, with a case having a TTF of more than 1 year. Molecular profiling reports of 16 afatinib-resistant biopsy samples were available, and the secondary T790M mutation was detected in one patient with L833V/H835L mutation and one harboring S768I/L858R mutation.
CONCLUSIONS
Our findings suggested that afatinib is effective in patients with uncommon mutations. Mechanisms of afatinib resistance vary and need further investigation.
Topics: Adenocarcinoma of Lung; Adult; Afatinib; Aged; Aged, 80 and over; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Retrospective Studies
PubMed: 34549528
DOI: 10.1111/1759-7714.14156 -
Targeted Oncology May 2022Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with advanced and recurrent EGFR-positive non-small...
The Difference in Clinical Outcomes Between Osimertinib and Afatinib for First-Line Treatment in Patients with Advanced and Recurrent EGFR-Mutant Non-Small Cell Lung Cancer in Taiwan.
BACKGROUND
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are the standard first-line treatment for patients with advanced and recurrent EGFR-positive non-small cell lung cancer.
OBJECTIVE
The main objective of the present study was to compare the clinical efficacies between osimertinib and afatinib as first-line treatment in patients with EGFR-mutant non-small cell lung cancer.
METHODS
We retrospectively analyzed patients with advanced and recurrent non-small cell lung cancer who harbored an exon 19 deletion or an exon 21 L858R mutation and were being given either osimertinib or afatinib as first-line treatment from January 2018 to December 2020.
RESULTS
A total of 128 patients were selected for this study. The osimertinib group included 47 patients, while 81 patients received afatinib. The median follow-up time was 20.1 months in the osimertinib group and 22.7 months in the afatinib group. The median progression-free survival was 18.8 months and 13.1 months in the osimertinib and afatinib groups, respectively (hazard ratio 0.75 [95% confidence interval 0.48-1.18]). The median overall survival was not reached in the osimertinib group and was 41.7 months in the afatinib group (hazard ratio 0.79 [95% confidence interval 0.36-1.72]). In patients without brain metastasis, the median progression-free survival was 17.9 months and 17.2 months in the osimertinib and afatinib groups, respectively (hazard ratio 1.02 [95% confidence interval 0.56-1.85]). In patients with brain metastasis at baseline, the median progression-free survival was 22.1 months in the osimertinib group, and 10.9 months in the afatinib group (adjusted hazard ratio 0.45 [95% confidence interval 0.21-0.96]).
CONCLUSIONS
Our research demonstrates that there was no strong evidence showing that patients taking osimertinib as first-line treatment experienced longer median progression-free survival and overall survival than patients treated with afatinib. However, there was a statistical significance revealing that osimertinib provided better median progression-free survival than afatinib in patients with brain metastasis at baseline.
Topics: Acrylamides; Afatinib; Aniline Compounds; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Indoles; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Taiwan
PubMed: 35460474
DOI: 10.1007/s11523-022-00878-x -
Veterinary Research Communications Dec 2023Canine glioma is one of the most common brain tumors with poor prognosis, making effective chemotherapy highly desirable. Previous studies have suggested that ERBB4, a...
Canine glioma is one of the most common brain tumors with poor prognosis, making effective chemotherapy highly desirable. Previous studies have suggested that ERBB4, a signaling molecule involving one of the epidermal growth factor receptors (EGFR), may be a promising therapeutic target. In this study, the anti-tumor effects of pan-ERBB inhibitors, which can inhibit the phosphorylation of ERBB4, were evaluated both in vitro and in vivo using a canine glioblastoma cell line. The results demonstrated that both afatinib and dacomitinib effectively reduced the expression of phosphorylated ERBB4, and significantly decreased the number of viable cells, ultimately prolonging the survival time of orthotopically xenografted mice. Further downstream of ERBB4, afatinib was found to suppress the expression of phosphorylated Akt and phosphorylated Extracellular signal-related kinases1 and 2 (ERK1/2) and induced apoptotic cell death. Thus, pan-ERBB inhibition is a promising therapeutic strategy for the treatment of canine gliomas.
Topics: Animals; Dogs; Mice; Afatinib; ErbB Receptors; Signal Transduction; Phosphorylation; Glioma; Cell Line, Tumor; Dog Diseases
PubMed: 36991174
DOI: 10.1007/s11259-023-10117-x -
Die Pharmazie Feb 2022Patients with prostate cancer often develop resistance to androgen deprivation therapy, a condition called castration-resistant prostate cancer (CRPC). Enzalutamide...
Patients with prostate cancer often develop resistance to androgen deprivation therapy, a condition called castration-resistant prostate cancer (CRPC). Enzalutamide (MDV3100) can prolong the survival of patients with CRPC after chemotherapy, but ∼50% of patients eventually relapse and develop resistance to MDV3100. Thus, it is necessary to explore new treatment methods to improve the therapeutic effect of MDV3100. Tyrosine kinases play an essential role in the pathogenesis of CRPC. MTT assay was used to detect the inhibitory effects of MDV3100 and tyrosine kinase inhibitor on prostate cancer cells. CompuSyn version 1.0 was used to calculate the combination index (CI) values using the Chou-Talalay method. Clone formation and EdU assay were used to detect the effect of afatinib combined with MDV3100 on the proliferation of 22Rv1 cells. RT-qPCR and Western blot were used to explore the mechanism of drug combination. The aim of the present study was to determine the effects of several tyrosine kinase inhibitors (TKIs) when used in combination with MDV3100 . The results demonstrated that TKIs combined with MDV3100 exerted a synergistic effect on a variety of PCa cells. Afatinib combined with MDV3100 could suppress the proliferation and migration of 22RV1 cells, as well as cause their cell cycle arrest and apoptosis. Mechanistically, afatinib effectively reduced the protein expression levels of HER2 and HER3 and inhibited EGFR phosphorylation, thereby enhancing the effect of MDV3100 and suppressing CRPC. These findings suggested that afatinib treatment improved the effect of MDV3100 on 22RV1 cells, highlighting this drug as a potential therapeutic strategy for patients with CRPC.
Topics: Afatinib; Androgen Antagonists; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Recurrence, Local; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 35209965
DOI: 10.1691/ph.2022.1948 -
BMC Health Services Research Apr 2022Guidelines in 2013 and 2014 recommended Epidermal Growth Factor Receptor (EGFR) testing for metastatic lung adenocarcinoma patients as the efficacy of targeted therapies...
BACKGROUND
Guidelines in 2013 and 2014 recommended Epidermal Growth Factor Receptor (EGFR) testing for metastatic lung adenocarcinoma patients as the efficacy of targeted therapies depends on the mutations. However, adherence to these guidelines and the corresponding costs have not been well-studied.
METHODS
We identified 2362 patients at least 65 years old newly diagnosed with metastatic lung adenocarcinoma from January 2013 to December 2015 using the SEER-Medicare database. We examined the utilization patterns of EGFR testing and targeted therapies including erlotinib and afatinib. We further examined the costs of both EGFR testing and targeted therapy in terms of Medicare costs and patient out-of-pocket (OOP) costs.
RESULTS
The EGFR testing rate increased from 38% in 2013 to 51% and 49% in 2014 and 2015 respectively. The testing rate was 54% among the 394 patients who received erlotinib, and 52% among the 42 patients who received afatinib. The median Medicare and OOP costs for testing were $1483 and $293. In contrast, the costs for targeted therapy were substantially higher with median 30-day costs at $6114 and $240 for erlotinib and $6239 and $471 for afatinib.
CONCLUSION
This population-based study suggests that testing guidelines improved the use of EGFR testing, although there was still a large proportion of patients receiving targeted therapy without testing. The costs of targeted therapy were substantially higher than the testing costs, highlighting the need to improve adherence to testing guidelines in order to improve clinical outcomes while reducing the economic burden for both Medicare and patients.
Topics: Adenocarcinoma of Lung; Afatinib; Aged; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Medicare; Mutation; Protein Kinase Inhibitors; United States
PubMed: 35397521
DOI: 10.1186/s12913-022-07857-y