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Molecules (Basel, Switzerland) Jan 2024Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of...
Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of chemoresistant cells represents a major challenge in chemotherapy. Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity. Additionally, we confirmed that dacomitinib inhibits chemoresistance in paclitaxel-resistant ovarian cancer HeyA8-MDR cells. Collectively, our research indicated that dacomitinib effectively resensitized paclitaxel in SKOV3-TR cells by inhibiting EGFR signaling and elevating intracellular ROS levels.
Topics: Female; Humans; Paclitaxel; Reactive Oxygen Species; Ovarian Neoplasms; Apoptosis; ErbB Receptors; Fluoresceins; Quinazolinones
PubMed: 38202856
DOI: 10.3390/molecules29010274 -
Frontiers in Pharmacology 2023According to the 2023 guidelines for treating non-small-cell lung cancer (NSCLC), first-line treatment and recently developed agents for the treatment of epidermal...
Comparison of the efficacy and safety of first-line treatments for of advanced EGFR mutation-positive non-small-cell lung cancer in Asian populations: a systematic review and network meta-analysis.
According to the 2023 guidelines for treating non-small-cell lung cancer (NSCLC), first-line treatment and recently developed agents for the treatment of epidermal growth factor (EGFR) mutation-positive locally advanced or metastatic NSCLC were compared in this meta-analysis. Treatment regimens involved in the included studies included first, second, and third-generation tyrosine kinase inhibitors (TKIs), TKIs plus chemotherapy, TKIs plus angiogenesis inhibitors, and platinum-containing doublet chemotherapy with or without bevacizumab. Considering the varying efficacy and safety of drugs in people of different ethnic origins, the optimal regimen should be determined, and the safety of first-line treatments should be assessed in the Asian population specifically. PubMed, Embase, the Cochrane Library, Web of Science, and the China National Knowledge Infrastructure (CNKI) were systematically searched to retrieve reports on randomized controlled trials (RCTs) with research data published from inception to 1 February 2023. Adopting Asian patient populations as the target (including studies in which Asian patients accounted for more than 50% of the sample), a network meta-analysis (NMA) was conducted for comparison of treatment regimens and treatments were ranked based on the surface under the cumulative ranking curve (SUCRA). A total of 19 RCTs involving 5,824 patients and covering 14 treatment regimens were included. The primary outcome measure examined in this study was progression-free survival (PFS); other outcome measures examined were overall survival (OS), disease control rate (DCR), objective response rate (ORR), occurrence of any adverse events (AE), occurrence of adverse events of grade 3 or above (≥3AE), and occurrence of serious adverse events (SAE). In terms of PFS, all regimens including TKIs (as a monotherapy or in combination with other therapies), as well as bevacizumab (Bev) plus chemotherapy (Ch) were found to be significantly superior to basic chemotherapy (HRs: 0.09-0.61, < 0.05 in all cases compared with Ch alone). The highest-ranking therapies were erlotinib (Erl) plus Bev (SUCRA: 0.94) and Erl plus ramucirumab (Ram) (SUCRA: 0.93). Regarding OS, no significant differences was observed between first-line treatment strategies; the top four treatments based on SUCRA, in rank order, were Bev + Ch (0.87), gefitinib (Gef) plus Ch (0.81), dacomitinib (Dac) (0.79), and osimertinib (Osi) (0.69). Additionally, there were no significant differences between first-line treatment strategies in terms of DCR. Regarding ORR, the top three treatments based on SUCRA were Erl + Bev (0.85), Erl + Ram (0.76), and Gef + Ch (0.74). No significant difference between first-line treatment strategies was observed in terms of the risk of AE. However, based on SUCRA, Erl ranked highest on avoidance of ≥ 3AE (0.97), and Osi ranked highest on avoidance of SAE (0.91). Based on these analyses of survival benefits, tumor burden response, and safety, furmonertinib (Fur), Osi, and aumolertinib (Aum) may represent the best treatment regimen options for Asian patients, significantly prolonging survival (as measured by median PFS/OS), eliciting a greater tumor burden response, and exposing patients to a lower risk of adverse events. Although Erl + Bev and Erl + Ram are associated with the best survival benefits in terms of PFS, further clinical studies are still needed to identify ways to reduce the risk of adverse events. https://www.crd.york.ac.uk/prospero/display_record.php? ID=CRD42023407994, identifier CRD42023407994.
PubMed: 37484016
DOI: 10.3389/fphar.2023.1212313 -
The prognostic significance and potential mechanism of DBF4 zinc finger in hepatocellular carcinoma.Scientific Reports May 2024DBF4 zinc finger (DBF4) is a critical component involved in DNA replication and cell proliferation. It acts as a positive regulator of the cell division cycle 7 kinase....
DBF4 zinc finger (DBF4) is a critical component involved in DNA replication and cell proliferation. It acts as a positive regulator of the cell division cycle 7 kinase. In this study, our investigation encompassed the impact of DBF4 on hepatocellular carcinoma (HCC) progression and delved into the potential mechanisms. We utilized open-access databases like TCGA and GEO to analyze the association between DBF4 and 33 different tumor types. We also conducted immunohistochemistry experiments to validate the expression of DBF4 in HCC, STAD, COAD, READ, PAAD, and LGG. Furthermore, we employed lentiviral transduction to knockdown DBF4 in HLF and SMMC cells, as well as to overexpress DBF4 in Huh7 cells. Subsequently, we evaluated the impact of DBF4 on proliferation, migration, and invasion of hepatocellular carcinoma cells. RNA sequencing and KEGG pathway enrichment analysis were also conducted to identify potential pathways, which were further validated through WB experiments. Finally, pathway inhibitor was utilized in rescue experiments to confirm whether DBF4 exerts its effects on tumor cells via the implicated pathway. Our findings revealed that DBF4 exhibited significant expression levels in nearly all examined tumors, which were further substantiated by the results of immunohistochemistry analysis. High DBF4 expression was correlated with poor overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI), disease-free interval (DFI), relapse-free interval (RFI) in majority of tumor types, particularly in patients with HCC. In vitro experiments demonstrated that inhibition of DBF4 impaired the proliferative, migratory, and invasive abilities of HCC cells, whereas overexpression of DBF4 promoted these phenotypes. Sequencing results indicated that DBF4 may induce these changes through the ERBB signaling pathway. Further experimental validation revealed that DBF4 activates the ERBB signaling pathway, leading to alterations in the JNK/STAT, MAPK, and PI3K/AKT signaling pathways, thereby impacting the proliferative, migratory, and invasive abilities of tumor cells. Lastly, treatment of Huh7 cells overexpressing DBF4 with the ERBB2 inhibitor dacomitinib demonstrated the ability of ERBB2 inhibition to reverse the promoting effect of DBF4 overexpression on the proliferative, migratory, and invasive abilities of HCC cells. DBF4 plays a pivotal oncogenic role in HCC by promoting the ERBB signaling pathway and activating its downstream PI3K/AKT, JNK/STAT3, and MAPK signaling pathways. DBF4 may serve as a prognostic biomarker for patients with HCC.
Topics: Female; Humans; Male; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Prognosis; Signal Transduction; Zinc Fingers; Cell Cycle Proteins
PubMed: 38724606
DOI: 10.1038/s41598-024-60342-w -
Journal of Immunotherapy and Precision... Aug 2023Osimertinib is the treatment of choice for epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC). Because of its high price, many... (Review)
Review
INTRODUCTION
Osimertinib is the treatment of choice for epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC). Because of its high price, many low-income countries, such as Syria, cannot provide osimertinib, which makes it difficult to choose the appropriate treatment for these patients. This study aimed to review articles that assessed tyrosine kinase inhibitors (TKIs) for advanced NSCLC and developed an appropriate treatment plan for Syrian patients.
METHODS
An electronic literature search was conducted of published phase II and III studies that assessed the efficacy of EGFR-TKIs for advanced NSCLC between January 2003 and May 2022.
RESULTS
Seventeen articles were reviewed. The results were similar when erlotinib or icotinib was compared with gefitinib. Progression-free survival and overall survival for afatinib and dacomitinib were longer than for gefitinib, with small significant differences. Osimertinib was the only TKI that showed efficacy against the T790M mutation, which showed an improvement over the first- and second-generation TKIs. Osimertinib as a first-line therapy is not cost-effective compared with first- and second-generation TKIs.
CONCLUSION
Osimertinib is the preferred first-line treatment in patients with advanced mutated NSCLC. First- and second-generation TKIs are still considered good options, especially in low-income countries that cannot cover the costs of osimertinib.
PubMed: 37637235
DOI: 10.36401/JIPO-22-29 -
ESMO Open Dec 2023Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC)...
INTRODUCTION
Dacomitinib showed superior progression-free survival (PFS) and overall survival compared to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations in the ARCHER1050 study. However, because that study did not include patients with brain metastases, the efficacy of dacomitinib in patients with brain metastases has not been clarified.
PATIENTS AND METHODS
This single-arm phase II study enrolled 30 patients with treatment-naïve advanced NSCLC harboring activating EGFR mutations from January 2021 to June 2021 and started them on dacomitinib (45 mg/day). All patients had non-irradiated brain metastases with a diameter of ≥5 mm. The primary endpoint was confirmed intracranial objective response rate (iORR).
RESULTS
Patients had exon 19 deletions (46.7%) and L858R mutations in exon 21 (55.3%). The confirmed iORR was 96.7% (29/30), with an intracranial complete response of 63.3%. Median intracranial PFS (iPFS) was not reached, with 12- and 18-month iPFS rates of 78.6% [95% confidence interval (CI) 64.8% to 95.4%] and 70.4% (95% CI 54.9% to 90.1%), respectively. In the competing risk analysis, the 12-month cumulative incidence of intracranial progression was 16.7%. Regarding the overall efficacy for intracranial and extracranial lesions, the overall ORR was 96.7%, and the median PFS was 17.5 months (95% CI 15.2 months-not reached). Grade 3 or higher treatment-related adverse events were reported in 16.7% of patients, and 83.3% required a reduced dacomitinib dose to manage adverse events. However, none permanently discontinued dacomitinib treatment due to treatment-related adverse events.
CONCLUSIONS
Dacomitinib has outstanding intracranial efficacy in patients with EGFR-mutant NSCLC with brain metastases.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Brain Neoplasms
PubMed: 38016250
DOI: 10.1016/j.esmoop.2023.102068 -
OncoTargets and Therapy 2024rearrangements are recognized drivers in lung cancer, representing a small subset (1-2%) of non-small cell lung cancer (NSCLC). Additionally, fusions also serve as a...
rearrangements are recognized drivers in lung cancer, representing a small subset (1-2%) of non-small cell lung cancer (NSCLC). Additionally, fusions also serve as a rare acquired resistance mechanism in -mutant NSCLC. Only a few NSCLC cases have been reported with co-occurrence of mutations and fusions as an acquired resistance mechanism induced by EGFR-tyrosine kinase inhibitors (TKIs). A 68-year-old man diagnosed with lung adenocarcinoma harboring L858R mutation initially responded well to dacomitinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI). Afterward, he developed acquired resistance accompanied by a rearrangement. Next-generation sequencing (NGS) analysis revealed that the tumor possessed both the new fusion and the L858R mutation. Subsequently, he was treated with a combination of cisplatin, pemetrexed, and bevacizumab resulting in a partial response. Nevertheless, his condition deteriorated as the disease progressed, manifesting as hydrocephalus, accompanied by altered consciousness and lower limb weakness. The subsequent combined treatment with dacomitinib and selpercatinib resulted in a significant improvement in neurological symptoms. Here, we first identified acquired fusion with a coexisting L858R mutation following dacomitinib treatment. Our findings highlight the importance of NGS for identifying fusions and suggest the potential combination of dacomitinib and selpercatinib to overcome this resistance. For NSCLC patients with rearrangements and no access to RET inhibitors, pemetrexed-based chemotherapy provides a feasible alternative.
PubMed: 38911906
DOI: 10.2147/OTT.S470946 -
Nature Communications Apr 2024Targeting neovascularization in glioblastoma (GBM) is hampered by poor understanding of the underlying mechanisms and unclear linkages to tumour molecular landscapes....
Targeting neovascularization in glioblastoma (GBM) is hampered by poor understanding of the underlying mechanisms and unclear linkages to tumour molecular landscapes. Here we report that different molecular subtypes of human glioma stem cells (GSC) trigger distinct endothelial responses involving either angiogenic or circumferential vascular growth (vasectasia). The latter process is selectively triggered by mesenchymal (but not proneural) GSCs and is mediated by a subset of extracellular vesicles (EVs) able to transfer EGFR/EGFRvIII transcript to endothelial cells. Inhibition of the expression and phosphorylation of EGFR in endothelial cells, either pharmacologically (Dacomitinib) or genetically (gene editing), abolishes their EV responses in vitro and disrupts vasectasia in vivo. Therapeutic inhibition of EGFR markedly extends anticancer effects of VEGF blockade in mice, coupled with abrogation of vasectasia and prolonged survival. Thus, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new therapeutic target in a subset of GBMs.
Topics: Humans; Animals; Mice; Endothelial Cells; Glioma; Glioblastoma; ErbB Receptors; Extracellular Vesicles; Neoplastic Stem Cells; Brain Neoplasms
PubMed: 38570528
DOI: 10.1038/s41467-024-46597-x -
BMC Cancer Oct 2023About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to...
BACKGROUND
About 10% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are harbored as uncommon mutations. This study aimed to explore the efficacy and safety of dacomitinib, a second-generation EGFR tyrosine kinase inhibitor (EGFR-TKIs), in treating uncommon EGFR-mutated advanced NSCLC.
METHODS
Treatment-naïve advanced NSCLC patients treated with dacomitinib at Hunan Cancer Hospital with uncommon EGFR mutations were evaluated. The primary endpoint was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety.
RESULT
Between December 2019 and December 2021, a total of 16 patients was included. Median PFS was 14.0 (95% CI 4.32-23.7) months, and median OS was not reached. ORR was 68.8% (95% CI 41.3 to 89.0%) and DCR was 93.8% (95%CI 69.8 to 99.8%), including three achieving complete remission (CR) and eight achieving partial remission (PR). Median PFS for patients with brain metastasis was 9.0 (95%CI 6.9 to 11.1) months. Intracranial ORR was 100%, including 2 CR and 4 PR. Major treatment-related adverse events (TRAEs) included rash (87.5%), paronychia (62.5%), oral ulcers (50.0%), and diarrhea (50.0%), none of which were ≥ grade 3 TRAEs.
CONCLUSIONS
Dacomitinib showed good activity and manageable toxicity in NSCLC patients with uncommon EGFR mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Cohort Studies; Antineoplastic Agents; Protein Kinase Inhibitors; ErbB Receptors; Mutation
PubMed: 37840124
DOI: 10.1186/s12885-023-11465-2 -
Translational Lung Cancer Research May 2024
PubMed: 38854932
DOI: 10.21037/tlcr-24-193 -
Neuro-oncology Advances 2023Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as...
BACKGROUND
Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as epidermal growth factor receptor () amplified and ~50% also are mutant positive. In a previously reported multicenter phase II study, we have described the response of recurrent GBM (rGBM) patients to dacomitinib, an EGFR tyrosine kinase inhibitor (TKI). As a continuation of that report, we leverage the tumor cargo-encapsulating extracellular vesicles (EVs) and explore their genetic composition as carriers of tumor biomarker.
METHODS
Serum samples were longitudinally collected from EGFR-amplified rGBM patients who clinically benefitted from dacomitinib therapy (responders) and those who did not (nonresponders), as well as from a healthy cohort of individuals. The serum EV transcriptome was evaluated to map the RNA biotype distribution and distinguish GBM disease.
RESULTS
Using long RNA sequencing, we show enriched detection of over 10 000 coding RNAs from serum EVs. The EV transcriptome yielded a unique signature that facilitates differentiation of GBM patients from healthy donors. Further analysis revealed genetic enrichment that enables stratification of responders from nonresponders prior to dacomitinib treatment as well as following administration.
CONCLUSION
This study demonstrates that genetic composition analysis of serum EVs may aid in therapeutic stratification to identify patients with dacomitinib-responsive GBM.
PubMed: 37811539
DOI: 10.1093/noajnl/vdad104