The oncogenic EGFR-SHC1 fusion confers insensitivity to EGFR-TKI via dual activation of N-EGFR kinase domain and C-SHC1 phosphorylation sites in lung cancer

While epidermal growth factor receptor (EGFR) fusions in non-small cell lung cancer (NSCLC) typically show sensitivity to tyrosine kinase inhibitors (TKIs), 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 setting. 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 NSCLC patient with EGFR-SHC1. This study illustrates a cooperative oncogenesis between kinase and scaffold protein in fusions, providing a clinically actionable strategy for overcoming TKI resistance in patients with these oncogenic fusions.