Phosphoproteomics Reveals EPHA2 and EGFR Activation Following Wnt Pathway Inhibition in Wnt-Driven Tumours

ABSTRACT: Wnt signalling represses multiple receptor tyrosine kinases (RTKs) in Wnt-high cancers. To identify RTKs responsible for MAPK activation following Wnt pathway inhibition, phosphotyrosine-targeted mass spectrometry was performed on xenograft tumour samples derived from HPAF-II and HCT116 cells. Tumours were treated with the PORCN inhibitor ETC-159 or generated from TCF7L2 knockout cells to achieve pharmacological or genetic suppression of Wnt signalling. Immunoaffinity enrichment of phosphotyrosine-containing peptides followed by LC-MS/MS analysis identified increased phosphorylation of EPHA2, EGFR and ERBB2 upon Wnt inhibition. Functional studies demonstrated that EGFR acts as a convergent mediator linking Wnt inhibition and EPHA2 loss to MAPK activation. These data provide insight into RTK signalling rewiring in Wnt-driven tumours and identify therapeutic vulnerabilities involving EGFR and Wnt pathway co-targeting.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

SUBMITTER: Changyuan Hu  

LAB HEAD: David M. Virshup

PROVIDER: PXD079682 | Pride | 2026-08-20

REPOSITORIES: Pride