CircCDYL2 promotes trastuzumab resistance via sustaining HER2 downstream signaling in breast cancer

Yun Ling,Qiang Liu,Chang Gong,Qing Luo,Qun Lin,Xiaolin Fang,Shijie Jia,Erwei Song,Yinghuan Cen,Maryam Mehrpour,Juanmei Li,Wanyi Lin,Yu Shi,Gehao Liang,Ahmed Hamai,Zihao Liu,Wenqian Yang,Jun Li

doi:10.1186/s12943-021-01476-7

Abstract

BackgroundApproximate 25% HER2-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly. However, the mechanisms underlying trastuzumab resistance remained largely unclear.MethodsTrastuzumab-resistant associated circRNAs were identified by circRNAs high-throughput screen and qRT-PCR in HER2+ breast cancer tissues with different trastuzumab response. The biological roles of trastuzumab-resistant associated circRNAs were detected by cell vitality assay, colony formation assay, Edu assay, patient-derived xenograft (PDX) models and orthotopic animal models. For mechanisms research, the co-immunoprecipitation, Western blot, immunofluorescence, and pull down assays confirmed the relevant mechanisms of circRNA and binding proteins.ResultsWe identified a circRNA circCDYL2, which was overexpressed in trastuzumab-resistant patients, which conferred trastuzumab resistance in breast cancer cells in vitro and in vivo. Mechanically, circCDYL2 stabilized GRB7 by preventing its ubiquitination degradation and enhanced its interaction with FAK, which thus sustained the activities of downstream AKT and ERK1/2. Trastuzumab-resistance of HER2+ BC cells with high circCDYL2 could be reversed by FAK or GRB7 inhibitor. Clinically, HER2+ BC patients with high levels of circCDYL2 developed rapid recurrence and had shorter disease-free survival (DFS) and overall survival (OS) following anti-HER2 therapy compared to those with low circCDYL2.ConclusionscircCDYL2-GRB7-FAK complex plays a critical role in maintaining HER2 signaling, which contributes to trastuzumab resistance and circCDYL2 is a potential biomarker for trastuzumab-resistance in HER2+ BC patients.

Highlights

Approximate 25% human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly
CircRNA deep RNA sequencing was performed in cohort 1, which included five patients were sensitive to trastuzumab and five patients were resistant to trastuzumab after antiHER2 therapy (Fig. 1A, Table S2)
The CircRNA deep RNA sequencing analysis revealed that a total of 3498 circular RNA (circRNA), including 3356 upregulated circRNAs and 138 downregulated circRNAs, were dysregulated in the trastuzumab-sensitive breast cancer tissues compared to the trastuzumab-resistant tissues

Summary

Introduction

Approximate 25% HER2-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly. The mechanisms underlying trastuzumab resistance remained largely unclear. Breast cancer (BC) is the most common malignant tumor globally with a 0.3% increasing rate per year [1]. Among these BC patients, 15–20% exhibits amplification/overexpression of human epidermal growth factor receptor 2 (HER2), subtyped as HER2-positive (HER2+). The prognosis of H ER2+ patients is largely favourable with the use of trastuzumab, 25–40% HER2+ patients still suffer recurrence and metastasis due to trastuzumab resistance [2, 4]. HER2+ BC patients with intrinsic trastuzumab-resistance have short survival-benefit from alternative anti-HER2 drugs, which accounts for a high rate of death [5]. It is of great significance to elucidate the mechanism of trastuzumab resistance in HER2+ BC

Methods

Results

Discussion

Conclusion