Data from The Oncogenic EGFR–SHC1 Fusion Confers Insensitivity to EGFR-TKIs via Dual Activation of N-EGFR Kinase Domain and C-SHC1 Phosphorylation Sites in Lung Cancer

作者：Jiani Zheng, Shen Zhao, Jianhua Zhan, Weitao Zhuang, Maojian Chen, Wei Jiang, Yihua Huang, Junyi He, Liyang Hu, Lanlan Pang, Feng Hao, Jinhui Xue, Mengting Shi, Anlin Li, Jingxun Wu, Shaodong Hong, Yuanyuan Zhao, Feng Ye, Yan Huang, Hongyun Zhao, Yunpeng Yang, Wenfeng Fang, Li Zhang, Jing Li · 年份：2026 · DOI：10.1158/2159-8290.c.8630783 · 研究领域：Cancer research、Biology、Chemistry、Cell biology

<div>Abstract Although epidermal growth factor receptor (EGFR) fusions in non–small cell lung cancer (NSCLC) typically show sensitivity to tyrosine kinase inhibitors (TKI), we identified an EGFR–SHC1 fusion subtype that exhibits intrinsic resistance to EGFR-TKI monotherapy through a dual-activation mechanism in the preclinical and clinical settings. EGFR–SHC1 fusion protein comprises of N-terminal EGFR and C-terminal SHC1. We demonstrated that EGFR–SHC1 simultaneously activates the EGFR kinase domain (KD) and SRC-mediated phosphorylation of the SHC1 fusion partner, thereby driving ERK/AKT pathway activation and tumorigenesis independent of KD inhibition. Structural modeling coupled with domain-specific mutagenesis revealed that SHC1 phosphorylation establishes a kinase-independent bypass mechanism. Notably, dual-targeted inhibition using afatinib (EGFR-TKI) in combination with dasatinib (SRC-TKI) induced marked tumor regression in a TKI-refractory patient with NSCLC with EGFR–SHC1. This study illustrates a cooperative oncogenesis between kinases and scaffold proteins in fusions, providing a clinically actionable strategy for overcoming TKI resistance in patients with these oncogenic fusions. Significance:This study identifies a previously unrecognized mode of oncogenic signaling in receptor tyrosine kinase (RTK) fusions, in which a non-kinase fusion partner actively d...