scholarly journals Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
M. Janusz Mezynski ◽  
Angela M. Farrelly ◽  
Mattia Cremona ◽  
Aoife Carr ◽  
Clare Morgan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Somatic Mutations ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Erbb Family ◽  
Gastric Tumour ◽  
Pi3k Signalling ◽  
Trial Setting

Abstract Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05). Conclusions PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting.

scholarly journals Overexpression of GSE1 Related to Trastuzumab Resistance in Gastric Cancer Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Wenbin Wang ◽  
Shuanhu Wang ◽  
A. man Xu ◽  
Xiao Yuan ◽  
Liguo Huang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Clinical Stage ◽  
Coiled Coil ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Patients ◽  
High Level

Gastric cancer is one of the most prevalent human cancers with poor prognosis. Trastuzumab is a well-used targeted drug for gastric cancer with HER2 amplification. Trastuzumab resistance restrains the clinical use of trastuzumab. In this study, we reported human Gse1 coiled-coil protein (GSE1) promoted trastuzumab resistance in HER2-positive gastric cancer cells. Acquired trastuzumab-resistant gastric cancer cells overexpressed GSE1, and depletion of GSE1 decreased the trastuzumab resistance of trastuzumab-resistant gastric cancer cells. BCL-2 was a downstream gene positively regulated by GSE1 and also performed promoting the role of trastuzumab resistance in HER2-positive gastric cancer cells. A high level of GSE1 was associated with a high risk of tumor lymph node metastasis and higher clinical stage in HER2-positive gastric cancer patients. GSE1 was a potential target that could be used for HER2-positive gastric cancer therapy.

scholarly journals The tRNA-derived fragment 5026a inhibits the proliferation of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Linwen Zhu ◽  
Zhe Li ◽  
Xiuchong Yu ◽  
Yao Ruan ◽  
Yijing Shen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Gastric Cancer Cells ◽  
Qrt Pcr

Abstract Background Recently, tRNA-derived fragments (tRFs) have been shown to serve important biological functions. However, the role of tRFs in gastric cancer has not been fully elucidated. This study aimed to identify the tumor suppressor role of tRF-5026a (tRF-18-79MP9P04) in gastric cancer. Methods Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was first used to detect tRF-5026a expression levels in gastric cancer tissues and patient plasma. Next, the relationship between tRF-5026a levels and clinicopathological features in gastric cancer patients was assessed. Cell lines with varying tRF-5026a levels were assessed by measuring tRF-5026a using qRT-PCR. After transfecting cell lines with a tRF-5026a mimic or inhibitor, cell proliferation, colony formation, migration, apoptosis, and cell cycle were evaluated. The expression levels of related proteins in the PTEN/PI3K/AKT pathway were also analyzed by Western blotting. Finally, the effect of tRF-5026a on tumor growth was tested using subcutaneous tumor models in nude mice. Results tRF-5026a was downregulated in gastric cancer patient tissues and plasma samples. tRF-5026a levels were closely related to tumor size, had a certain diagnostic value, and could be used to predict overall survival. tRF-5026a was also downregulated in gastric cancer cell lines. tRF-5026a inhibited the proliferation, migration, and cell cycle progression of gastric cancer cells by regulating the PTEN/PI3K/AKT signaling pathway. Animal experiments showed that upregulation of tRF-5026a effectively inhibited tumor growth. Conclusions tRF-5026a (tRF-18-79MP9P04) is a promising biomarker for gastric cancer diagnostics and has tumor suppressor effects mediated through the PTEN/PI3K/AKT signaling pathway.

scholarly journals Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Maria Gaibar ◽  
Laura Beltrán ◽  
Alicia Romero-Lorca ◽  
Ana Fernández-Santander ◽  
Apolonia Novillo
Keyword(s):  
Breast Cancer ◽  
Somatic Mutations ◽  
Tyrosine Kinase Domain ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Trastuzumab Resistance ◽  
Her2 Gene ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

Liquid biopsies to track trastuzumab resistance in metastatic HER2-positive gastric cancer

Gut ◽  
2018 ◽  
Vol 68 (7) ◽  
pp. 1152-1161 ◽  
Author(s):  
De-Shen Wang ◽  
Ze-Xian Liu ◽  
Yun-Xin Lu ◽  
Hua Bao ◽  
Xue Wu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
In Situ Hybridisation ◽  
Targeted Sequencing ◽  
In Vivo Studies ◽  
Fluorescence In Situ Hybridisation ◽  
Trastuzumab Resistance ◽  
Liquid Biopsies ◽  
Her2 Positive

ObjectiveTo monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer (mGC).DesignTargeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+  to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes.ResultsThe results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of HER2 gene were highly consistent with fluorescence in situ hybridisation data, and the detected HER2 SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance. PIK3CA mutations were significantly enriched in patients with innate resistance, and ERBB2/4 genes were the most mutated genes, accounting for trastuzumab resistance in six (35.3%) and five (29.4%) patients in baseline and progression plasma, respectively. Patients with PIK3CA/R1/C3 or ERBB2/4 mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in NF1 contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance.ConclusionLongitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.

scholarly journals PS2 - 167 CIC Deficiency is Associated with Dysregulation of Genes Involved in Cell Adhesion and Developmental Processes

2016 ◽  
Vol 43 (S4) ◽  
pp. S13-S13
Author(s):  
V.G. LeBlanc ◽  
S. Chittaranjan ◽  
M. Firme ◽  
S.Y. Chan ◽  
J. Song ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Lines ◽  
Somatic Mutations ◽  
Control Cell ◽  
The Cancer Genome Atlas ◽  
Mitogen Activated Protein Kinase ◽  
Low Grade ◽  
Type I ◽  
Developmental Processes

Somatic mutations in the Capicua (CIC) gene were first identified in Type I low-grade gliomas (LGGs), which are characterized by 1p/19q co-deletions and IDH mutations. They are found at frequencies of ~50-70% in this glioma subtype, and have since been identified in ~40% of stomach adenocarcinomas (STADs) of the microsatellite instability (MSI) subtype; however, the role of these somatic mutations in malignancy has yet to be established. In Drosophila, CIC functions as a transcriptional repressor whose activity is inhibited upon activation of the mitogen-activated protein kinase (MAPK) signalling pathway. Though mammalian CIC appears to retain these functions, only three of its target genes have been established in human cells: ETV1, ETV4, and ETV5 (ETV1/4/5). To further probe CIC’s transcriptional network, we developed CIC knockout cell lines and performed transcriptomic and proteiomic analyses in these and in control cell lines expressing wild type CIC, identifying a total of 582 differentially expressed genes. We also used RNA-seq data from The Cancer Genome Atlas (TCGA) for Type I LGGs and STADs to perform additional differential expression analyses between CIC-deficient and CIC-expressing samples. Though gene-level overlap was limited between the three contexts, we found that CIC appears to regulate the expression of genes involved in cell-cell adhesion, metabolism, and developmental processes in all three contexts. These results shed light on the pathological role of CIC mutations and may help explain why these have been associated with poorer outcome within Type I LGGs.

scholarly journals Synthetic miR-143 Inhibits Growth of HER2-Positive Gastric Cancer Cells by Suppressing KRAS Networks Including DDX6 RNA Helicase

2019 ◽  
Vol 20 (7) ◽  
pp. 1697 ◽  
Author(s):  
Yoshihisa Tokumaru ◽  
Toshihiro Tajirika ◽  
Nobuhiko Sugito ◽  
Yuki Kuranaga ◽  
Haruka Shinohara ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Ectopic Expression ◽  
Rna Helicase ◽  
Her2 Overexpression ◽  
Significant Finding ◽  
Her2 Positive ◽  
Gastric Cancer Cells ◽  
Cancer Breast

Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.

scholarly journals Circular RNA hsa_circ_0001829 promotes gastric cancer progression through miR-155-5p/SMAD2 axis

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Qiuling Niu ◽  
Zhijie Dong ◽  
Min Liang ◽  
Yuanwei Luo ◽  
Hai Lin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Gain Of Function

Abstract Background Accumulating evidences have shown that circular RNAs (circRNAs) play important roles in regulating the pathogenesis of cancer. However, the role of circRNAs in gastric cancer (GC) remains largely unclear. Methods In this study, we identified a novel upregulated circRNA, hsa_circ_0001829, in chemically induced malignant transformed human gastric epithelial cells using RNA-seq. Subsequent qRT-PCR and ISH assays were performed to detect the expression level of hsa_circ_0001829 in GC cell lines and tissues. Functional roles of hsa_circ_0001829 in GC were then explored by loss- and gain-of- function assays. Bioinformatic prediction and luciferase assay were used to investigate potential mechanisms of hsa_circ_0001829. Finally, the mice xenograft and metastasis models were constructed to assess the function of hsa_circ_0001829 in vivo. Results We found that hsa_circ_0001829 was significantly upregulated in GC tissues and cell lines. Loss- and gain-of- function assays showed that hsa_circ_0001829 promotes GC cells proliferation, migration and invasion, and the affected cell cycle progression and apoptosis rates may account for the effect of hsa_circ_0001829 on GC proliferation. In addition, bioinformatic prediction and luciferase assay showed that hsa_circ_0001829 acts as a molecular sponge for miR-155-5p and that SMAD2 was a target gene of miR-155-5p; moreover, hsa_circ_0001829 sponges miR-155-5p to regulate SMAD2 expression and hsa_circ_0001829 promotes GC progression through the miR-155-5p–SMAD2 pathway. Finally, suppression of hsa_circ_0001829 expression inhibited tumor growth and aggressiveness in vivo. Conclusion Taken together, our findings firstly demonstrated a novel oncogenic role of hsa_circ_0001829 in GC progression through miR-155-5p–SMAD2 axis, and our study may offer novel biomarkers and therapeutic targets for GC.

Sign in / Sign up

Export Citation Format

Share Document