A combined screening approach involving an image-based green fluorescent protein-Grb2 translocation assay and a mammalian membrane two-hybrid protein–protein interaction assay identified 11 novel interactors of EGFR. Eight of those were further confirmed by co-immunoprecipitation. TACC3 was identified as a novel EGFR interactor, which specifically binds to oncogenic EGFR variants. TACC3 directly modulates EGFR stability at the cell surface and hence promotes mitogen-activated protein kinase signaling. Targeting TACC3 in non-small cell lung cancer cells partially resensitizes TK-resistant cells to TK inhibitors.