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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 -
Biomedicine & Pharmacotherapy =... Jul 2024The lesson from many studies investigating the efficacy of targeted therapy in glioblastoma (GBM) showed that a future perspective should be focused on combining...
The lesson from many studies investigating the efficacy of targeted therapy in glioblastoma (GBM) showed that a future perspective should be focused on combining multiple target treatments. Our research aimed to assess the efficacy of drug combinations against glioblastoma stem cells (GSCs). Patient-derived cells U3042, U3009, and U3039 were obtained from the Human Glioblastoma Cell Culture resource. Additionally, the study was conducted on a GBM commercial U251 cell line. Gene expression analysis related to receptor tyrosine kinases (RTKs), stem cell markers and genes associated with significant molecular targets was performed, and selected proteins encoded by these genes were assessed using the immunofluorescence and flow cytometry methods. The cytotoxicity studies were preceded by analyzing the expression of specific proteins that serve as targets for selected drugs. The cytotoxicity study using the MTS assay was conducted to evaluate the effects of selected drugs/candidates in monotherapy and combinations. The most cytotoxic compounds for U3042 cells were Disulfiram combined with Copper gluconate (DSF/Cu), Dacomitinib, and Foretinib with IC values of 52.37 nM, 4.38 µM, and 4.54 µM after 24 h incubation, respectively. Interactions were assessed using SynergyFinder Plus software. The analysis enabled the identification of the most effective drug combinations against patient-derived GSCs. Our findings indicate that the most promising drug combinations are Dacomitinib and Foretinib, Dacomitinib and DSF/Cu, and Foretinib and AZD3759. Since most tested combinations have not been previously examined against glioblastoma stem-like cells, these results can shed new light on designing the therapeutic approach to target the GSC population.
Topics: Humans; Glioblastoma; Neoplastic Stem Cells; Drug Repositioning; Protein Kinase Inhibitors; Cell Line, Tumor; Receptor Protein-Tyrosine Kinases; Brain Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents; Cell Survival
PubMed: 38876048
DOI: 10.1016/j.biopha.2024.116892 -
Translational Lung Cancer Research May 2024
PubMed: 38854932
DOI: 10.21037/tlcr-24-193 -
Targeted Oncology Jun 2024Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer....
BACKGROUND
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain the frontline standard of care for patients with EGFR-mutant non-small cell lung cancer. An updated toxicity profile of EGFR-TKIs proves valuable in guiding clinical decision making.
OBJECTIVE
This study comprehensively assessed the risk of EGFR-TKI-related adverse events (AEs) involving different systems/organs.
METHODS
We systematically searched PubMed, Embase, Web of Science, and Cochrane library for phase III randomized controlled trials comparing EGFR-TKI monotherapy with placebo or chemotherapy in patients with non-small cell lung cancer. The odds ratio (OR) of all-grade and high-grade adverse events (AEs) including dermatologic, gastrointestinal, hematologic, hepatic, and respiratory events was pooled for a meta-analysis. Subgroup analyses based on the control arm (placebo or chemotherapy) and individual EGFR-TKIs (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) were conducted.
RESULTS
Thirty-four randomized controlled trials comprising 15,887 patients were included. The pooled OR showed EGFR-TKIs were associated with a significantly increased risk of all-grade dermatologic AEs including paronychia, pruritus, rash, skin exfoliation, and skin fissures, gastrointestinal AEs including abdominal pain, diarrhea, dyspepsia, mouth ulceration, and stomatitis, hepatic AEs including elevated alanine aminotransferase and aspartate aminotransferase, and respiratory AEs including epistaxis, interstitial lung disease and rhinorrhea. Furthermore, a significantly increased risk of high-grade rash (OR 7.83, 95% confidence interval [CI] 5.11, 12.00), diarrhea (OR 2.10, 95% CI 1.44, 3.05), elevated alanine aminotransferase (OR 3.93, 95% CI 1.71, 9.03), elevated aspartate aminotransferase (OR 3.22, 95% CI 1.05, 9.92) and interstitial lung disease (OR 2.35, 95% CI 1.38, 4.01) was observed in patients receiving EGFR-TKIs. When stratified by individual EGFR-TKIs, gefitinib showed a significant association with all-grade and high-grade hepatotoxicity and interstitial lung disease.
CONCLUSIONS
Epidermal growth factor receptor tyrosine kinase inhibitors were associated with a significantly increased risk of various types of AEs. Clinicians should be vigilant about the risks of these EGFR-TKI-related AEs, particularly for severe hepatotoxicity and interstitial lung disease, to facilitate early detection and proper management.
PubMed: 38824269
DOI: 10.1007/s11523-024-01073-w -
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 -
Heliyon May 2024A775_G776insYVMA, the typical and predominant exon 20 insertion variant in non-small cell lung cancer, exhibits relative insensitivity to covalent -targeted tyrosine...
A775_G776insYVMA, the typical and predominant exon 20 insertion variant in non-small cell lung cancer, exhibits relative insensitivity to covalent -targeted tyrosine kinase inhibitors. However, other less common insertions have shown better responses to -targeted inhibitors. M774delinsWLV is a rare exon 20 insertion subtype and its clinical sensitivity to -targeted inhibitors remains unclear. Furthermore, there is a lack of current studies to elucidate its structure and predict its sensitivity to -targeted tyrosine kinase inhibitors. Herein, we presented a case of non-small cell lung cancer harboring M774delinsWLV who derived favorable response and significant survival benefit from -targeted tyrosine kinase inhibitors. A 60-year-old male with metastatic lung adenocarcinoma carrying M774delinsWLV received pyrotinib monotherapy as first-line treatment. After rapid disease progression at three months, sequential combination therapy with pyrotinib and bevacizumab yielded promising antitumor activity and sustained progression-free survival benefits for nearly a year. Subsequent dacomitinib monotherapy displayed significant activity against this uncommon insertion, resulting in a rapid decrease in tumor markers and partial response, along with progression-free survival of one year. The molecular simulation revealed no significant differences in the overall protein structure and binding pocket region between M774delinsWLV and the wild type. Drug binding dynamics simulation indicated that dacomitinib exhibited the most potent binding activity compared to afatinib, pyrotinib and poziotinib. Conclusively, dacomitinib exhibited promising efficacy against the rare exon 20 insertion M774delinsWLV. Extensive investigation is needed to elucidate the effects of -targeted tyrosine kinase inhibitors on non-small cell lung cancer with different insertion subtypes.
PubMed: 38707278
DOI: 10.1016/j.heliyon.2024.e30312 -
Frontiers in Oncology 2024Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing...
BACKGROUND
Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing exon 19 deletion and exon 21 L858R point mutations. However, EGFR TKI resistance inevitably develops. The optimal subsequent therapy remains to be identified, although platinum-containing chemotherapy regimens are often administered. Our objectives were to describe baseline characteristics, survival, and subsequent treatment patterns for patients with advanced nonsquamous NSCLC with exon 19 deletion or L858R mutation who received a platinum-based combination regimen after front-line EGFR TKI therapy.
METHODS
This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Data cut-off was 30-June-2022. The Kaplan-Meier method was used to estimate overall survival (OS) after initiation of pemetrexed-platinum (n=119) or any platinum-based combination regimen (platinum cohort; n=311).
RESULTS
The two cohorts included two-thirds women (65%-66%) and 57%-58% nonsmokers; median ages were 66 and 65 years in pemetrexed-platinum and platinum cohorts, respectively. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study.
CONCLUSION
The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with -mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.
PubMed: 38699642
DOI: 10.3389/fonc.2024.1285280 -
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 -
Spectrochimica Acta. Part A, Molecular... Jun 2024Dacomitinib is a highly selective second-generation tyrosine kinase inhibitor that can irreversibly bind to tyrosine kinase and is mainly used in the treatment of lung...
Dacomitinib is a highly selective second-generation tyrosine kinase inhibitor that can irreversibly bind to tyrosine kinase and is mainly used in the treatment of lung cancer. The binding characteristics of dacomitinib with human α 1-acid glycoprotein (HAG) were analyzed by multispectral and computational simulation techniques. The fluorescence spectra showed that dacomitinib can quench the fluorescence of HAG by forming the HAG-dacomitinib complex with a molar ratio of 1:1 (static quenching). At the temperature similar to that of the human body, the affinity of dacomitinib to HAG (8.95 × 10 M) was much greater than that to BSA (3.39 × 10 M), indicating that dacomitinib will give priority to binding onto HAG. Thermodynamics parameters analysis and driving force competition experiments showed that hydrogen bonding and hydrophobic forces were the major sources for keeping the complex of HAG-dacomitinib stable. The experimental outcomes also showed that the binding of dacomitinib can lead to the loosening of the skeleton structure of HAG, which led to a slight change in the secondary structure, and also reduces the hydrophobicity of the microenvironment of Trp and Tyr residues. The binding sites of dacomitinib on HAG and the contribution of key amino acid residues to the binding reaction were determined by molecular docking and molecular dynamics (MD) simulation. In addition, it was found that there was a synergistic effect between dacomitinib and Mg and Co ions. Mg and Co could increase the K of dacomitinib to HAG and prolong the half-life of dacomitinib.
Topics: Humans; Protein Binding; Molecular Docking Simulation; Orosomucoid; Binding Sites; Thermodynamics; Spectrometry, Fluorescence; Circular Dichroism; Quinazolinones
PubMed: 38554689
DOI: 10.1016/j.saa.2024.124197 -
Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants.Nature Communications Mar 2024The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different...
The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.
Topics: Humans; Glioblastoma; Protein Kinase Inhibitors; ErbB Receptors; Lung Neoplasms; Mutation
PubMed: 38548752
DOI: 10.1038/s41467-024-45594-4