Targeting the HER2-ELF3-KRAS axis: a novel therapeutic strategy for KRASG13D colorectal cancer. Academic Article uri icon

Overview

abstract

  • Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, with KRAS mutations playing a significant role in its tumorigenesis. Among the KRAS variants, the G13D mutation is associated with poor prognosis and distinctive biological behaviors. This study focuses on the role of HER2, a critical prognostic and predictive biomarker, in modulating the unique characteristics of KRASG13D-mutated CRCs. We identified a novel transcriptional regulatory network involving HER2, ELF3, and KRAS, with ELF3 acting as a key transcription factor (TF) that regulates KRAS expression under conditions of HER2 overexpression. Our findings reveal that this HER2-ELF3-KRAS axis is exclusively activated in KRASG13D, driving aggressive oncogenic features and conferring resistance to cetuximab (CTX) therapy. Through comprehensive analysis of gene expression profiles, we demonstrated that HER2 is a crucial therapeutic target specifically for KRASG13D CRCs. To explore this further, we introduced YK1, a small molecule inhibitor designed to disrupt the ELF3-MED23 interaction, leading to the transcriptional downregulation of HER2 and KRAS. This intervention significantly attenuated the HER2-ELF3-KRAS axis, sensitizing KRASG13D CRCs to CTX and reducing their tumorigenic potential by inhibiting the epithelial-to-mesenchymal transition process. Our study underscores the importance of HER2 as a key determinant in the unique biological characteristics of KRASG13D CRCs and highlights the therapeutic potential of targeting the HER2-ELF3-KRAS axis. By presenting YK1 as a novel pharmacological approach, we provide a promising strategy for developing tailored interventions for KRASG13D CRCs, contributing to the ongoing efforts in precision medicine for CRCs.

authors

  • Hwang, Soo Yeon
  • Seo, Yoojeong
  • Park, Seojeong
  • Kim, Seul-Ah
  • Moon, Inhye
  • Liu, Yi
  • Kim, Seojeong
  • Pak, Eun Seon
  • Jung, Sehyun
  • Kim, Hyeyoon
  • Jeon, Kyung-Hwa
  • Seo, Seung Hee
  • Sung, Inyoung
  • Lee, Heetak
  • Park, So-Yeon
  • Na, Younghwa
  • Kim, Tae Il
  • Kwon, Youngjoo

publication date

  • May 9, 2025

Research

keywords

  • Colorectal Neoplasms
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-ets
  • Proto-Oncogene Proteins p21(ras)
  • Receptor, ErbB-2
  • Transcription Factors

Identity

PubMed Central ID

  • PMC12063335

Scopus Document Identifier

  • 105004478059

Digital Object Identifier (DOI)

  • 10.1186/s12943-025-02343-5

PubMed ID

  • 40340861

Additional Document Info

volume

  • 24

issue

  • 1