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

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 drives tumorigenesis through kinase-independent mechanisms. By challenging the classical kinase-centric model of RTK fusions, it provides a framework for understanding intrinsic resistance to TKIs and for developing rational combination therapies. See related commentary by Le and Wolf, p. 1480.