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Mol. Cancer, 09 May 2025 | https://doi.org/10.1186/s12943-025-02343-5 Targeting the HER2-ELF3-KRAS axis: a novel therapeutic strategy for KRASG13D colorectal cancer

Soo‑Yeon Hwang ¹, Yoojeong Seo ³, Seojeong Park 1, Seul‑Ah Kim ^1,2, Inhye Moon ^1,2, Yi Liu ¹, Seojeong Kim¹, Eun Seon Pak ¹, Sehyun Jung ¹, Hyeyoon Kim ¹, Kyung‑Hwa Jeon ¹, Seung Hee Seo ¹, Inyoung Sung ⁴, Heetak Lee ⁵, So‑Yeon Park ¹, Younghwa Na ⁶, Tae Il Kim ³ and Youngjoo Kwon ^1,2,*

¹College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
²Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul 03760, Republic of Korea.
³Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun‑Gu, Seoul 03722, Republic of Korea.
⁴BK21 FOUR Intelligence Computing, Seoul National University, Seoul, Republic of Korea.
⁵Center for Genome Engineering, Institute for Basic Science, 55, Expo‑Ro, Yuseong‑Gu, Daejeon 34126, Republic of Korea.
⁶College of Pharmacy, CHA University, Pocheon 11160, Republic of Korea.

^*Corresponding author: correspondence to Youngjoo Kwon

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 KRAS^G13D-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 KRAS^G13D, 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 KRAS^G13D 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 KRAS^G13D 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 KRAS^G13D 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 KRAS^G13D CRCs, contributing to the ongoing efforts in precision medicine for CRCs.

논문정보

형식Research article
게재일2025년 05월 (BRIC 등록일 2025-05-09)
연구진국내 연구진
분야 의약학 > 종양의학

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