Abstract
Trastuzumab 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.
Highlights
Gastric cancer (GC) is the 5th most commonly diagnosed malignancy and the 3rd leading cause of cancer mortality around the world [1]
To study whether trastuzumab resistance has resulted from endoplasmic reticulum (ER) To find out the molecular mechanism involved in miR-301a-3p stress in Human epidermal growth factor receptor 2 (HER2)-positive GC cells, NCI-N87 was incubated with the mediating trastuzumab resistance, bioinformatics analyses were
Accumulating researchers have found that ER stress confers the ability to cope with stress to cancer cells, resulting in drug resistance [23, 24]
Summary
Gastric cancer (GC) is the 5th most commonly diagnosed malignancy and the 3rd leading cause of cancer mortality around the world [1]. Human epidermal growth factor receptor 2 (HER2) amplification or overexpression affects ~6.1–23.0% of GC patients [2]. In comparison with using chemotherapy alone, ToGA trial showed that adding trastuzumab (Herceptin, Roche), an effective anti-HER2 humanized monoclonal antibody, in traditional chemotherapy could noticeably increase progression-free survival and overall survival in HER2-positive GC [3]. In patients with HER2positive GC, therapies combining with trastuzumab have become a standard first-line treatment. Some patients could not receive satisfactory effects after these therapies, and cancer progressed rapidly in three to four months with a poor prognosis [3, 4]. The underlying molecular mechanism of trastuzumab resistance in HER2-positive GC is still unclear, and the availability of surrogate markers to predict resistance remains an unmet need
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