FOXK2/SH2D3A axis recruits EGFR to drive papillary thyroid cancer progression and confers sensitivity to EGFR inhibition.

Papillary thyroid carcinoma (PTC) is the most prevalent malignant tumor of the endocrine system, yet the specific role of Forkhead box protein K2 (FOXK2) in its progression remains incompletely elucidated. Analyses based on public databases and 31 pairs of matched clinical specimens revealed that both FOXK2 and SH2D3A were significantly upregulated in PTC tissues and cell lines, with their expression levels showing a strong positive correlation. Functional experiments indicated that knockdown of FOXK2 or SH2D3A markedly inhibited PTC cell proliferation, invasion, and migration while reducing the phosphorylation of p38, ERK, and AKT. In FOXK2-knockdown cells, SH2D3A overexpression partially restored these oncogenic phenotypes and the activation of downstream signaling, a result further validated in nude mouse xenograft models. Mechanistically, FOXK2 was found to enhance SH2D3A transcription by directly binding to its promoter region. Co-immunoprecipitation assays further confirmed that SH2D3A directly interacts with the epidermal growth factor receptor (EGFR). Importantly, pharmacological inhibition of EGFR with Gefitinib effectively suppressed the activation of EGFR and ERK, thereby attenuating the oncogenic activity of the FOXK2/SH2D3A axis. Collectively, this study identifies a novel FOXK2/SH2D3A/EGFR signaling axis that contributes to PTC progression and may represent a potential therapeutic vulnerability in aggressive papillary thyroid cancer.