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

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.

Exosomal miR-301a-3p from esophageal squamous cell carcinoma cells promotes angiogenesis by inducing M2 polarization of macrophages via the PTEN/PI3K/AKT signaling pathway

“…miR-301a-3p, belonging to the mir-130/301 family, is a multifunctional miRNA that promotes tumor progression, regulates inflammatory responses, and mediates drug resistance [ 28 – 30 ]. miR-301a-3p can promote tumor proliferation and metastasis in several malignancies, including esophageal, pancreatic, and colorectal cancer [ 31 – 33 ].…”

FGFR1 Amplification and Response to Neoadjuvant Anti-HER2 Treatment in Early HER2-Positive Breast Cancer

“…Although the mechanisms whereby FGFR prevents trastuzumab binding have not yet been determined, recent studies have unveiled the relevant role of micro-RNAs in gastric cancer HER2-positive cells. Guo et al proposed that miR-301a-3p disseminated TZ resistance by activating the expression of FGFR1 through the intercellular transfer of this micro-RNA by exosomes [27].…”

Resistance mechanisms to HER2-targeted therapy in gastroesophageal adenocarcinoma: A systematic review

“…In response to HER2 targeting, other receptors can compensate for HER2 loss by maintaining activation of shared downstream pathways. Ten studies demonstrated MET receptor upregulation following inhibition of the HER2 receptor in resistant models [46][47][48][49][50][51][52][53][54][55], whilst others described the contributions of other ErbB receptor family members (n = 7) [28,37,46,[56][57][58][59], fibroblast growth factor receptors (FGFR) (n = 4) [34,[60][61][62], or other receptors (n = 6) [36,52,61,[63][64][65].…”