scholarly journals miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jing Guo ◽  
Xuxian Zhong ◽  
Qinglin Tan ◽  
Shengnan Yang ◽  
Jiaqi Liao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Endoplasmic Reticulum ◽  
Growth Factor ◽  
Er Stress ◽  
Growth Factor Receptor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Non Invasive ◽  
Underlying Mechanisms ◽  
Leucine Rich Repeats

AbstractTrastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.

scholarly journals Study of Human Epidermal Growth Factor Receptor 2 (HER2) Expression in Gastric Carcinoma

2020 ◽  
Vol 7 (47) ◽  
pp. 2747-2751
Author(s):  
Lekshmi Vijayakumaran Nair Lilly ◽  
Geetha Sukumaran
Keyword(s):  
Gastric Cancer ◽  
Growth Factor ◽  
Gastric Carcinoma ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Intestinal Type ◽  
Treatment Modalities ◽  
Her2 Overexpression ◽  
Her2 Expression ◽  
Her2 Positive

BACKGROUND Gastric carcinoma is an important cause of cancer related mortality worldwide. Majority of the patients are diagnosed in the advanced stage of the disease. The main treatment modalities are surgery and chemotherapy, but the survival rate of patients with advanced resectable gastric cancer remains poor. For patients with unresectable gastric cancer, chemotherapy remains the treatment of choice. Into this scenario comes the importance of newer targeted therapeutic agents which improve survival rates with acceptable toxicity effects. HER2 is a growth factor implicated in disease initiation and progression, and its expression is associated with a poor prognosis. The aim of this study is detection of HER2 expression in gastric carcinoma and evaluate its relationship with the histopathological characteristics. This would be the stepping stone for patients with tumours that are HER2 positive who could benefit from targeted therapeutical agents like Trastuzumab. METHODS Gastrectomy specimens which were diagnosed as Gastric Carcinoma in the Department of Pathology, Government Medical College, Trivandrum, during a period of two years were included in this study. Routine Haematoxylin and Eosin staining and immunohistochemistry for HER2 were done. RESULTS Thirty eight cases of gastric carcinoma were received during the study period. Intestinal type adenocarcinoma formed the bulk of the tumours (68.42 %), followed by the diffuse type adenocarcinoma (18.42 %). Of the 38 cases, 10 cases showed HER2 positivity. All the positive cases were intestinal type of adenocarcinomas. CONCLUSIONS Our study concluded that 26 % of gastric carcinomas showed positive immunoreaction for HER2 and HER2 overexpression was more in intestinal type adenocarcinomas. HER2 overexpression was also associated with higher stage tumours. There was no association with the patient’s age, gender, location of tumour and tumour differentiation. KEYWORDS Gastric Carcinoma, HER2 expression, Immunohistochemistry, Lauren Classification

scholarly journals Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 400 ◽  
Author(s):  
Seiichiro Mitani ◽  
Hisato Kawakami
Keyword(s):  
Gastroesophageal Junction ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Drug Conjugates ◽  
Gastroesophageal Junction Cancer ◽  
Development Of Resistance ◽  
Epidermal Growth ◽  
Antibody Drug

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody–drug conjugates that are under development and have shown promising antitumor activity in early studies.

scholarly journals HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ilana Schlam ◽  
Sandra M. Swain
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

AbstractHuman epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

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.

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