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
Menée à l'aide de lignées cellulaires, de xénogreffes sur des modèles murins ainsi que d'échantillons tumoraux issus de patients atteints d'un cancer du poumon, cette étude met en évidence un mécanisme par lequel la fusion oncogène EGFR-SHC1 confère aux cellules cancéreuses une insensibilité aux inhibiteurs de tyrosine kinase du récepteur EGFR via l'activation du domaine kinase de l'EGFR et la phosphorylation de la protéine SHC1
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.
Cancer Discovery , résumé, 2026