MTPN drives noncanonical ERK hyperactivation in colorectal cancer and provides a promising therapeutic approach for precision medicine in CRC.

Efforts to block the mitogen-activated protein kinase (MAPK) pathway for colorectal cancer (CRC) therapy are challenged by frequent oncogenic mutations of its upstream genes, robust extracellular signal-regulated kinase (ERK) reactivation and difficulty in tumor-selective targeting without compromising the physiological processes of normal cells. Deeper insight into the precise mechanism of ERK regulation could help develop potential therapeutic strategies. Here, using integrated analyses of genomes, transcriptomes, and interactomes, we identified myotrophin (MTPN) as a crucial regulator of ERK. Further investigation using human CRC cells, xenograft models and tail vein metastasis models in nude mice and human CRC samples revealed that MTPN is involved in a noncanonical, endoplasmic-reticulum (ER)-associated mechanism that drives ERK activation in CRC. MTPN functions as a scaffold that mediates ERK binding to mitogen-activated protein kinase kinase (MEK) via a conserved ankyrin (ANK) domain, thereby promoting ERK-mediated malignancy phenotypes in CRC. MTPN is widely overexpressed in CRC tissues and is significantly correlated with hyperactivation of ERK and poor survival in patients with CRC. Targeting MTPN strikingly blocks ERK signaling without inducing ERK pathway reactivation, exhibiting a potent inhibitory effect on tumor growth and metastasis in a safe and stable manner. Our work reveals a crucial spatial regulatory mechanism that maintains ERK hyperactivation in CRC and highlights MTPN as a promising target for optimizing ERK-driven CRC therapy.