The Combination of Afatinib With Dasatinib or Miransertib Results in Synergistic Growth Inhibition of Stomach Cancer CellsAl-Janaby, Nahi, Seddon
et alWorld J Oncol (2024) 15 (2), 192-208
Abstract: Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of patients with stomach cancer. However, the duration of response may be short in many patients, with tumor heterogeneity being one contributing factor.We investigated the effect of various types of targeted agents on growth in vitro and migration of a panel of human stomach cancer cells (HSCCLs) and the impact of cell proliferation rate on the anti-tumor activities of these agents. We also investigated the association between the cell surface expression of the HER family members, hepatocyte growth factor receptor (c-Met), anaplastic lymphoma kinase (ALK)7 and cancer stem cell markers CD44 and CD133, and the response to the targeted agents.Of the 18 agents examined, the cyclin dependent kinase (CDK) 1/2/5/9 inhibitor dinaciclib was the most effective and inhibited the growth of all human HSCCLs at 50% inhibitory concentration (IC50) values between 9 nM to 23 nM. Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor (TKI) lapatinib and the EGFR-specific TKI erlotinib in inhibiting the growth of HSCCLs. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs, with the IC50 values ranging from 2 nM to 7 µM. Many of these agents were more effective in inhibiting the growth of HSCCLs when they were proliferating at a slower rate. Treatment with neratinib, afatinib, dinaciclib, dasatinib, stattic, miransertib and paclitaxel significantly inhibited migration of stomach cancer cells. Interestingly, treatment with a combination of afatinib and dasatinib or afatinib and miransertib resulted in synergistic and additive growth inhibition of stomach cancer cells.These results suggest that treatment with a combination of these agents may be of therapeutic value in stomach cancer and warrants further investigations.Copyright 2024, Al-Janaby et al.
Gene alternation of cerebrospinal fluid in patients with leptomeningeal metastases of lung adenocarcinoma using next-generation sequencingYang, Wen, Pan
et alBMC Cancer (2022) 22 (1), 580
Abstract: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) provide a better prognosis in EGFR-mutant non-small cell lung cancer (NSCLC). Nevertheless, the outcome of leptomeningeal metastasis (LM) remains poor. In addition, due to limited access to intracranial tumour tissue, gene alterations associated with leptomeningeal metastasis from lung adenocarcinoma (LM-LUAD) are unclear.Forty-five patients with LM-LUAD from May 2019 to June 2021 in Guangdong Sanjiu Brain Hospital were enrolled in this study. Seventy-five percent (34/45) of patients with LM harbored EGFR mutations, and patients with progressive disease (PD) of LM had 3rd-generation EGFR-TKI therapy and were defined as Cohort 1; those without 3rd-generation EGFR-TKI therapy were defined as Cohort 2. Next-generation targeted panel sequencing (NGS) was performed in each cerebrospinal fluid (CSF) sample of the two cohorts, and 9/45 LM-LUAD patients had matched plasma (PLA).The common gene alterations discovered in the CSF of LM-LUAD were EGFR mutation (34/45, 75%), TP53 (25/45, 56%), CDKN2A (9/45, 20%), ALK (7/45, 16%), CTNNB1 (6/45, 13%), MET (5/45, 11%), APC (4/45, 9%), FGF4 (4/45, 9%), FGF3 (4/45, 9%), ERBB2 (4/45, 9%), and PIK3CG (4/45, 9%). Cooccurring mutations of TP53 and EGFR were found in 49% (22/45) of patients and correlated with poor prognosis. CDKN2A was identified in 20% (9/45) of patients and presented slightly shorter overall survival (OS) than those without (7.1 versus 8.8 months, p = 0.2). Cohort 1 had more genes associated with poor prognosis, consisting of CDK4, CDKN2A, PIK3CG, or PIK3CA, and YES1 and MET were more likely to be detected in cohort 2. The alteration of EGFR was comparable between CSF and matched PLA. Incidences of gene alterations such as CDK4, CDKN2A, MET, SOX2, JAK2, BRAF, and PIK3CG were more likely to be identified in CSF. All mutant allele frequencies (MAF) were much higher in CSF than in matched PLA.CSF could be a potential candidate for the genetic profiling of LM-LUAD, demonstrating the genetic characteristics of LM in EGFR-mutated lung adenocarcinoma on diverse EGFR-TKI therapies.© 2022. The Author(s).
Resistance to Aflatoxin Accumulation in Maize Mediated by Host-Induced Silencing of the Aspergillus flavus Alkaline Protease (alk) GeneOmolehin, Raruang, Hu
et alJ Fungi (Basel) (2021) 7 (11)
Abstract: Aspergillus flavus is a fungal pathogen that infects maize and produces aflatoxins. Host-Induced Gene Silencing (HIGS) has been shown to reduce host infection by various fungal pathogens. Here, the A. flavus alkaline protease (alk) gene was targeted for silencing through HIGS. An RNAi vector carrying a portion of the alk gene was incorporated into the B104 maize genome. Four out of eight transformation events containing the alk gene, Alk-3, Alk-4, Alk-7 and Alk-9, were self-pollinated to T4/T6 generations. At T3, the Alk-transgenic lines showed up to 87% reduction in aflatoxin accumulation under laboratory conditions. T4 transgenic Alk-3 and Alk-7 lines, and T5 and T6 Alk-4 and Alk-9 showed an average of 84% reduction in aflatoxin accumulation compared to their null controls under field inoculations (p < 0.05). F1 hybrids of three elite maize inbred lines and the transgenic lines also showed significant improvement in aflatoxin resistance (p < 0.006 to p < 0.045). Reduced A. flavus growth and levels of fungal ß-tubulin DNA were observed in transgenic kernels during in vitro inoculation. Alk-4 transgenic leaf and immature kernel tissues also contained about 1000-fold higher levels of alk-specific small RNAs compared to null controls, indicating that the enhanced aflatoxin resistance in the transgenic maize kernels is due to suppression of A. flavus infection through HIGS of alk gene.
Comparison of PD-L1, EGFR, ALK, and ROS1 Status Between Surgical Samples and Cytological Samples in Non-Small Cell Lung CarcinomaEkin, Nart, Savaş
et alBalkan Med J (2021) 38 (5), 287-295
Abstract: The expression levels of Programmed death ligand-1 (PD-L1), epidermal growth factor receptor (EGFR), anaplastic lymphoma tyrosine kinase gene (ALK), and proto-oncogene tyrosineprotein kinase 1 ROS (ROS1) are important for targeted treatment selection in advanced lung cancer. Most patients with lung cancer are diagnosed at an advanced stage and have no chance of surgery. For this reason, the accuracy and reliability of cytology samples for detecting those markers is important in patients whose histological sampling cannot be performed.To test the compatibility of histological and cytological sample analysis results of EGFR, ALK, ROS1 and PDL-1 in patients with NSCLC and to determine the adequacy of cytological analysis for PD-L1 expression.Retrospective cross-sectional study.The results of 231 patients whose PD-L1 was studied in 2018 were analyzed retrospectively. We excluded 11 inappropriate samples. A total of 220 samples were distributed as follows; 66 (30.0%) cytology specimens, 64 (29.1%) small histology biopsies, and 90 (40.9%) surgical biopsies. EGFR, ALK, ROS1 and PD-L1 analysis were performed in 139, 134, 116, and 220 patients, respectively. Samples containing >400 cells were considered suitable for molecular cytological study.A total of 154 (70.0%) histological (surgical biopsy) and 66 (30.0%) cytology samples were analyzed. There was no statistically significant difference between histological and cytological samples in terms of cellular adequacy for all molecular markers [EGFR: 93.7% and 90.9% (P = .556), ALK: 97.8% and 95.3% (P = .436) , ROS1: 89.9% vs. 91.9% (P = .729), PD-L1: 95.5% vs. 92.4% (P = .364)]. There was no statistically significant difference in the expression positivity rates of all biomarkers between histological and cytological samples [EGFR: 9.0% vs. 2.5% (P = .018), ALK: 7.9% vs. 9.8% (P = .719), ROS1 : 1.4% vs. 2.9% (P = .591), PD-L1: 54.4% vs. 41.0% (P = .078)].The cellular adequacy of cytology specimens for molecular testing in patients with NSCLC is satisfactory. This study shows that EGFR, ALK, ROS-1 and PDL-1 expression rates in cytological samples are not statistically different from histological samples.
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