Activation of HER2-ELF3-KRAS axis specifically deteriorates KRASG13D mutant colorectal cancer


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Soo-Yeon Hwang1
1Ewha Womans University

Abstract

Background

Colorectal cancer (CRC) is generally characterized by accumulation of diverse genetic alterations. KRAS mutations are most importantly considered driving factors for CRC tumorigenesis. Unlike prior reports, many recent studies have begun to demonstrate isotype-dependent functional impacts of each KRAS variant. Particularly, KRASG13D has been described to exhibit unique features; some KRASG13D CRC patients exhibit worse prognosis but can also clinically benefit from anti-EGFR agents. Our study focused on clarifying HER2 as the key determinant of this phenomenon and establishing KRASG13D -selective inhibitory strategy.

Method

To assess the clinical significance of targeting HER2 in KRASG13D CRCs, we intensively analyzed public databases and grade III CRC patient samples. We additionally prepared HER2-silenced and -overexpressed CRC cells and applied various in vitro, in vivo assays for further evaluation.

Results

HER2 overexpression was directly associated with the poor prognosis of KRASG13D CRC patients by significantly promoting the EMT process. It also exhibited negative correlation with the cetuximab-sensitivity of KRASG13D CRCs. However, targeting the already overexpressed HER2 protein using trastuzumab was ineffective against KRASG13D CRC cell, while HER2 gene silencing induced favorable changes in their tumorigenic features and ameliorated the susceptibility to cetuximab. We newly found a transcriptional regulatory network of HER2-ELF3-KRAS, where ELF3 serves as a common transcription factor for both HER2 and KRAS. Thus, we identified a novel small molecule, BTCP, which downregulates HER2 at the transcriptional level by specifically interrupting ELF3-MED23 interaction. BTCP suppressed the gene expression of HER2, ELF3, and KRAS, inducing marked attenuation of total HER signaling in vitro and in vivo, eventually leading to a significant tumor regression.

Conclusion

Our findings demonstrate therapeutic relevance of regulating HER2 gene transcription as a critical strategy to overcome clinicopathological issues underlying KRASG13D CRCs. This may provide a valuable insight to the treatment landscape of KRAS mutant CRCs.