Brand Toni M, Iida Mari, Corrigan Kelsey L, Braverman Cara M, Coan John P, Flanigan Bailey G, Stein Andrew P, Salgia Ravi, Rolff Jana, Kimple Randall J, Wheeler Deric L
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, 1111 Highland Avenue, Madison, WI 53705, USA.
Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010, USA.
Sci Signal. 2017 Jan 3;10(460):eaag1064. doi: 10.1126/scisignal.aag1064.
The epidermal growth factor receptor (EGFR) is a therapeutic target in patients with various cancers. Unfortunately, resistance to EGFR-targeted therapeutics is common. Previous studies identified two mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Nuclear translocation of EGFR bypasses the inhibitory effects of cetuximab, and the receptor tyrosine kinase AXL mediates cetuximab resistance by maintaining EGFR activation and downstream signaling. Thus, we hypothesized that AXL mediated the nuclear translocation of EGFR in the setting of cetuximab resistance. Cetuximab-resistant clones of non-small cell lung cancer in culture and patient-derived xenografts in mice had increased abundance of AXL and nuclear EGFR (nEGFR). Cellular fractionation analysis, super-resolution microscopy, and electron microscopy revealed that genetic loss of AXL reduced the accumulation of nEGFR. SRC family kinases (SFKs) and HER family ligands promote the nuclear translocation of EGFR. We found that AXL knockdown reduced the expression of the genes encoding the SFK family members YES and LYN and the ligand neuregulin-1 (NRG1). AXL knockdown also decreased the interaction between EGFR and the related receptor HER3 and accumulation of HER3 in the nucleus. Overexpression of LYN and NRG1 in cells depleted of AXL resulted in accumulation of nEGFR, rescuing the deficit induced by lack of AXL. Collectively, these data uncover a previously unrecognized role for AXL in regulating the nuclear translocation of EGFR and suggest that AXL-mediated SFK and NRG1 expression promote this process.
表皮生长因子受体（EGFR）是多种癌症患者的治疗靶点。不幸的是，对EGFR靶向治疗产生耐药性很常见。先前的研究确定了对EGFR单克隆抗体西妥昔单抗耐药的两种机制。EGFR的核转位绕过了西妥昔单抗的抑制作用，受体酪氨酸激酶AXL通过维持EGFR激活和下游信号传导介导西妥昔单抗耐药。因此，我们假设AXL在西妥昔单抗耐药情况下介导EGFR的核转位。培养的非小细胞肺癌西妥昔单抗耐药克隆和小鼠体内患者来源的异种移植瘤中AXL和核EGFR（nEGFR）的丰度增加。细胞分级分离分析、超分辨率显微镜和电子显微镜显示，AXL的基因缺失减少了nEGFR的积累。SRC家族激酶（SFK）和HER家族配体促进EGFR的核转位。我们发现AXL敲低降低了编码SFK家族成员YES和LYN以及配体神经调节蛋白-1（NRG1）的基因表达。AXL敲低还减少了EGFR与相关受体HER3之间的相互作用以及HER3在细胞核中的积累。在AXL缺失的细胞中过表达LYN和NRG1导致nEGFR积累，挽救了因AXL缺乏引起的缺陷。总的来说，这些数据揭示了AXL在调节EGFR核转位中以前未被认识的作用，并表明AXL介导的SFK和NRG1表达促进了这一过程。
