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Cell Death & Disease Oct 2020Current treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival, however disease progression commonly ensues. In a previous study we...
Current treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival, however disease progression commonly ensues. In a previous study we identified afatinib and crizotinib in combination as a novel potential therapy for CMM independent of BRAF/NRAS mutation status. Herein, we elucidate the underlying mechanisms of the combination treatment effect to find biomarkers and novel targets for development of therapy that may provide clinical benefit by proteomic analysis of CMM cell lines and xenografts using mass spectrometry based analysis and reverse phase protein array. Identified candidates were validated using immunoblotting or immunofluorescence. Our analysis revealed that mTOR/Insulin signaling pathways were significantly decreased by the afatinib and crizotinib combination treatment. Both in vitro and in vivo analyses showed that the combination treatment downregulated pRPS6KB1 and pRPS6, downstream of mTOR signaling, and IRS-1 in the insulin signaling pathway, specifically ablating IRS-1 nuclear signal. Silencing of RPS6 and IRS-1 alone had a similar effect on cell death, which was further induced when IRS-1 and RPS6 were concomitantly silenced in the CMM cell lines. Silencing of IRS-1 and RPS6 resulted in reduced sensitivity towards combination treatment. Additionally, we found that IRS-1 and RPS6KB1 expression levels were increased in advanced stages of CMM clinical samples. We could demonstrate that induced resistance towards combination treatment was reversible by a drug holiday. CD171/L1CAM, mTOR and PI3K-p85 were induced in the combination resistant cells whereas AXL and EPHA2, previously identified mediators of resistance to MAPK inhibitor therapy in CMM were downregulated. We also found that CD171/L1CAM and mTOR were increased at progression in tumor biopsies from two matched cases of patients receiving targeted therapy with BRAFi. Overall, these findings provide insights into the molecular mechanisms behind the afatinib and crizotinib combination treatment effect and leverages a platform for discovering novel biomarkers and therapy regimes for CMM treatment.
Topics: Afatinib; Antineoplastic Agents; Crizotinib; Drug Resistance, Neoplasm; Humans; Melanoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Signal Transduction; Skin Neoplasms; TOR Serine-Threonine Kinases; Melanoma, Cutaneous Malignant
PubMed: 33082316
DOI: 10.1038/s41419-020-03097-2 -
The Oncologist May 2024The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how...
BACKGROUND
The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC.
PATIENTS AND METHODS
Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population.
RESULTS
Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths.
CONCLUSION
We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.
PubMed: 38761385
DOI: 10.1093/oncolo/oyae107 -
International Journal of Radiation... 2021Radioresistance is highly correlated with radiotherapy failure in clinical cancer treatment. In the current study, we sought to examine the efficacy of Celecoxib and...
PURPOSE
Radioresistance is highly correlated with radiotherapy failure in clinical cancer treatment. In the current study, we sought to examine the efficacy of Celecoxib and Afatinib co-treatment as radiosensitizers in the management of non-small cell lung cancer (NSCLC) A549 cells.
MATERIALS AND METHODS
Generally, A549 cells were cultured with the treatment of Celecoxib and/or Afatinib for 24 h. Then, the cells were exposed to irradiation at 2 Gy/min for 1 min. After the end of treatment, cell viability, clonogenic survival, apoptosis and Prostaglandin E2 (PGE2) Elisa assays were performed. Transcriptional levels of Cyclooxygenase-2 (COX-2) affected by Celecoxib and/or Afatinib were measured by RT-qPCR. Posttranscriptional level of epidermal growth factor receptor (EGFR)-related gene was measured by Western blotting analysis.
RESULTS
Here, we, for the first time, reported that the co-treatment of Celecoxib and Afatinib regulates the resistance of NSCLC A549 cells to radiation. The co-treatment of Celecoxib and Afatinib sensitized radiotherapy through the radiation-induced loss of cell viability and colony formation, as well as apoptosis. Mechanistically, Celecoxib and Afatinib-treated cells showed the inhibition of COX-2 and EGFR expression, which may be responsible for the A549 cells' increased resistance to radiation.
CONCLUSION
Our results suggested that Celecoxib and Afatinib regulate cell sensitivity to apoptosis, and thus modulate the resistance of NSCLC to radiation.
Topics: A549 Cells; Afatinib; Apoptosis; Carcinoma, Non-Small-Cell Lung; Celecoxib; Cell Survival; Cyclooxygenase 2; Dinoprostone; Drug Synergism; ErbB Receptors; Humans; Lung Neoplasms; Radiation Tolerance
PubMed: 33164600
DOI: 10.1080/09553002.2021.1846817 -
Pharmaceuticals (Basel, Switzerland) Dec 2022Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its radiosensitive effects in nasopharyngeal carcinoma (NPC). However, the detailed mechanism of...
BACKGROUND
Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its radiosensitive effects in nasopharyngeal carcinoma (NPC). However, the detailed mechanism of afatinib-mediated sensitivity to radiation is still obscure in NPC.
METHODS
Quantitative phosphorylated proteomics and bioinformatics analysis were performed to illustrate the global phosphoprotein changes. The activity of the CD44-Stat3 axis and Epithelial-Mesenchymal Transition (EMT)-linked markers were evaluated by Western blotting. Wound healing and transwell assays were used to determine the levels of cell migration upon afatinib combined IR treatment. Cell proliferation was tested by CCK-8 assay. A pharmacological agonist by IL-6 was applied to activate Stat3. The xenograft mouse model was treated with afatinib, radiation or a combination of afatinib and radiation to detect the radiosensitivity of afatinib in vivo.
RESULTS
In the present study, we discovered that afatinib triggered global protein phosphorylation alterations in NPC cells. Further, bioinformatics analysis indicated that afatinib inhibited the CD44-Stat3 signaling and subsequent EMT process. Moreover, functional assays demonstrated that afatinib combined radiation treatment remarkably impeded cell viability, migration, EMT process and CD44-Stat3 activity in vitro and in vivo. In addition, pharmacological stimulation of Stat3 rescued radiosensitivity and biological functions induced by afatinib in NPC cells. This suggested that afatinib reversed the EMT process by blocking the activity of the CD44-Stat3 axis.
CONCLUSION
Collectively, this work identifies the molecular mechanism of afatinib as a radiation sensitizer, thus providing a potentially useful combination treatment and drug target for NPC radiosensitization. Our findings describe a new function of afatinib in radiosensitivity and cancer treatment.
PubMed: 36678534
DOI: 10.3390/ph16010037 -
Cancer Research and Treatment Oct 2023This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor...
PURPOSE
This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor (EGFR)+ non-small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group).
MATERIALS AND METHODS
In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes.
RESULTS
The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5).
CONCLUSION
This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; ErbB Receptors; Protein Kinase Inhibitors; Mutation
PubMed: 37218139
DOI: 10.4143/crt.2023.493 -
Journal of the Formosan Medical... Dec 2022The prognosis of triple-negative breast cancer (TNBC) is worse and a major proportion of TNBC expresses epidermal growth factor receptor (EGFR). Afatinib can inhibit...
BACKGROUND
The prognosis of triple-negative breast cancer (TNBC) is worse and a major proportion of TNBC expresses epidermal growth factor receptor (EGFR). Afatinib can inhibit EGFR signal pathway; however, its treatment effect for TNBC is unknown. Thus, we aimed to assess the efficacy and biomarkers of afatinib in combination with paclitaxel in a neoadjuvant setting.
METHODS
Patients with stage II to III TNBC were enrolled. They received 40 mg of afatinib daily for 14 days, followed by daily afatinib and weekly paclitaxel (80 mg/m) every 21 days for four to six cycles. To explore the mechanisms of responsiveness and non-responsiveness, 409 cancer-associated genes were sequenced.
RESULTS
Twenty-one patients were enrolled and one patient achieved a complete clinical response; however, a 2 mm residual tumor was noted in the surgical specimen. Overall, 33.0% patients were responders. Fifteen patients received molecular testing. No activated mutation of EGFR or Her2 were found. Activated PI3K or JAK2 pathway were trended to associate with non-responder (p = 0.057). Mutation of homologous recombination (HR) genes were correlated with non-responsiveness (p = 0.005). Seven patients did not have altered PI3K, JAK2 or HR pathway; six (85.7%) of them were responder. Patients with the amplified DAXX gene was associated with a favorable trend of response (p = 0.109).
CONCLUSION
Adding afatinib to neoadjuvant paclitaxel generated a modest effect in TNBC. Exploratory molecular analysis suggested that activated PI3K, JAK2 pathways and mutation of HR genes were associated with therapeutic non-responsiveness, and amplification of DAXX genes was associated with responsiveness to afatinib in combination with paclitaxel.
Topics: Humans; Female; Neoadjuvant Therapy; Triple Negative Breast Neoplasms; Paclitaxel; Afatinib; Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Phosphatidylinositol 3-Kinases; Treatment Outcome
PubMed: 35752529
DOI: 10.1016/j.jfma.2022.05.015 -
Cell Death & Disease Jul 2021Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its antitumor effects in head and neck squamous cell carcinoma (HNSCC) by inducing intrinsic...
Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its antitumor effects in head and neck squamous cell carcinoma (HNSCC) by inducing intrinsic apoptosis through suppression of mTORC1. However, the detailed mechanism and biological significance of afatinib-induced autophagy in HNSCC remains unclear. In the present study, we demonstrated that afatinib induced mTORC1 suppression-mediated autophagy in HNSCC cells. Further mechanistic investigation revealed that afatinib stimulated REDD1-TSC1 signaling, giving rise to mTORC1 inactivation and subsequent autophagy. Moreover, ROS generation elicited by afatinib was responsible for the induction of the REDD1-TSC1-mTORC1 axis. In addition, pharmacological or genetic inhibition of autophagy sensitized HNSCC cells to afatinib-induced apoptosis, demonstrating that afatinib activated pro-survival autophagy in HNSCC cells. Importantly, in vitro and in vivo assays showed that afatinib caused enhanced apoptosis but weaker autophagy in stem-like HNSCC cells constructed by CDH1 knockdown. This suggested that blocking autophagy has the potential to serve as a promising strategy to target HNSCC stem cells. In conclusion, our findings suggested that the combination treatment with afatinib and autophagy inhibitors has the potential to eradicate HNSCC cells, especially cancer stem cells in clinical therapy.
Topics: Afatinib; Animals; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Head and Neck Neoplasms; Humans; Male; Mice, Inbred BALB C; Mice, Nude; Models, Biological; Neoplasm Proteins; Neoplastic Stem Cells; Reactive Oxygen Species; Squamous Cell Carcinoma of Head and Neck; Up-Regulation; Xenograft Model Antitumor Assays; Mice
PubMed: 34294686
DOI: 10.1038/s41419-021-04011-0 -
Aging Nov 2023Recent years have seen a sharp rise in the amount of research on the connection between oxidative stress, autophagy, and cancer cells. However, the significant functions...
Recent years have seen a sharp rise in the amount of research on the connection between oxidative stress, autophagy, and cancer cells. However, the significant functions of oxidative stress and autophagy-related genes (OARGs) in gastric cancer (GC) are yet to be investigated integrally. Therefore, it will be a new and promising concept to search for novel OARG-related biomarkers to predict the prognosis and treatment response of GC. First, we assessed changes in prognosis and tumor microenvironment (TME) characteristics across the various oxidative stress and autophagy-related modification patterns based on a detailed analysis of 17 OARGs with prognostic significance of 808 GC samples. We identified three distinct OARG alteration patterns which displayed unique biological characteristics and immune cell infiltration features. Using principal component analysis methods, the OARGscore was developed to evaluate the OARG modification patterns of certain tumors. The negative connection between OARGscore and immune cells was statistically significant. Increased survival, a higher incidence of mutations, and a better response to immunotherapy were all predicted to be related to patients' high-OARGscore. In addition, the candidate chemotherapeutic drugs were predicted using the oncoPredict program. The low-OARGscore group was predicted to benefit more from Ribociclib, Alisertib, Niraparib, Epirubicin, Olaparib, and Axitinib, while patients in the high-OARGscore group were predicted to benefit more from Afatinib, Oxaliplatin, Paclitaxel, 5-Fluorouracil, Dabrafenib and Lapatinib. Our findings offer a specific method for predicting a patient's prognosis and susceptibility to immunotherapy, as well as a promising insight of oxidative stress and autophagy in GC.
Topics: Humans; Stomach Neoplasms; Tumor Microenvironment; Autophagy; Fluorouracil; Afatinib; Prognosis
PubMed: 37950729
DOI: 10.18632/aging.205194 -
Thoracic Cancer Nov 2023The comparative efficacies of different generation tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung... (Meta-Analysis)
Meta-Analysis
Survival outcomes of east Asian patients with advanced non-small cell lung cancer treated with first-line EGFR tyrosine kinase inhibitors: A network meta-analysis of real-world evidence.
BACKGROUND
The comparative efficacies of different generation tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) remain largely unknown. Moreover, whether one EGFR-TKI confers superior survival remains unclear, especially in East Asians. We conducted a network meta-analysis (NMA) comparing the survival outcomes of East Asian patients with advanced NSCLC treated with first-line EGFR-TKIs.
METHODS
The NMA included observational real-world evidence studies on adult patients with EGFR-mutated advanced NSCLC who received first (gefitinib and erlotinib), second (afatinib), or third (osimertinib) generation EGFR-TKIs as frontline therapy. Studies were identified through an online bibliographic search of Medline articles in the PubMed, SCOPUS, Web of Science, and Cochrane Library databases.
RESULTS
For overall survival (OS), afatinib had significantly better hazard ratios (HRs) than osimertinib (HR: 0.46, 95% confidence interval [CI]: 0.23-0.91), gefitinib (HR: 0.56, 95% CI: 0.43-0.72), and erlotinib (HR: 0.71, 95% CI: 0.54-0.92). For progression-free survival (PFS), afatinib had significantly better HRs than gefitinib (HR: 0.45, 95% CI: 0.36-0.56) and erlotinib (HR: 0.63, 95% CI: 0.49-0.81). Moreover, afatinib was most likely to achieve the longest OS (81.3%), followed by erlotinib (13%), osimertinib, and gefitinib. Furthermore, afatinib was most likely to achieve the longest PFS (48.3%), followed by osimertinib (34.9%) and erlotinib.
CONCLUSIONS
This real-world evidence shows that afatinib confers better survival than other first-line EGFR-TKIs in East Asian patients with advanced NSCLC.
Topics: Adult; Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Gefitinib; Erlotinib Hydrochloride; Tyrosine Kinase Inhibitors; Lung Neoplasms; East Asian People; Network Meta-Analysis; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 37704454
DOI: 10.1111/1759-7714.15112 -
Future Oncology (London, England) Feb 2023EGFR is a protein on cells that helps control their growth and division. Mutations in the gene for EGFR can cause cancer, including some cases of non-small-cell lung... (Review)
Review
WHAT IS EGFR & WHAT IS AFATINIB?
EGFR is a protein on cells that helps control their growth and division. Mutations in the gene for EGFR can cause cancer, including some cases of non-small-cell lung cancer (NSCLC). Afatinib is a medicine that blocks mutated and helps kill cancer cells. Many different types of mutation have been identified in people with NSCLC. Over three quarters of cases are caused by two types of mutation, known as common mutations, but some cases are caused by unusual/uncommon mutations. People with NSCLC who have these unusual/ uncommon mutations are often excluded from clinical trials. Consequently, researchers don't really know how well medicines like afatinib work in these people.
WHAT IS THIS SUMMARY ABOUT?
This is a summary of a study reporting findings from a large database of people with non-small-cell lung cancer (also called NSCLC) who have unusual or uncommon changes in a gene called and who received afatinib. The researchers used the database to see how effective afatinib is in people who have different types of unusual mutation. Afatinib seems to work well in people with NSCLC who have not already been treated. Part of the study also looked at people who had received a similar treatment, called osimertinib, in the past compared to those who had not been treated with this medicine.
WHAT DID THE RESEARCHERS FIND?
The researchers found that afatinib works well in most people with NSCLC who have unusual/uncommon mutations, although it seems to work better against certain types of these mutations than others.
WHAT DO THE RESULTS OF THE STUDY MEAN?
The researchers concluded that afatinib is a treatment option for most people with NSCLC and unusual/uncommon mutations. It is important for doctors to identify the precise type of mutation in a tumor before starting treatment.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 36794564
DOI: 10.2217/fon-2022-0842