Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

KRAS Inhibitors Are Potential Prophylaxis for Colorectal Cancer Metachronous Metastasis

Yaoyu Guo
ORCID logo ,
Chuling Hu
,
Guojie Long
,
Du Cai
,
Zhaoliang Yu
,
Xingxing Huang
,
Zerong Cai
,
Peishan Hu
,
Yufeng Chen
,
Feng Gao
* ORCID logo ,
Xiaojian Wu
*
Version 1 : Received: 18 March 2024 / Approved: 19 March 2024 / Online: 21 March 2024 (03:50:20 CET)

How to cite: Guo, Y.; Hu, C.; Long, G.; Cai, D.; Yu, Z.; Huang, X.; Cai, Z.; Hu, P.; Chen, Y.; Gao, F.; Wu, X. KRAS Inhibitors Are Potential Prophylaxis for Colorectal Cancer Metachronous Metastasis. Preprints 2024, 2024031095. https://doi.org/10.20944/preprints202403.1095.v1 Guo, Y.; Hu, C.; Long, G.; Cai, D.; Yu, Z.; Huang, X.; Cai, Z.; Hu, P.; Chen, Y.; Gao, F.; Wu, X. KRAS Inhibitors Are Potential Prophylaxis for Colorectal Cancer Metachronous Metastasis. Preprints 2024, 2024031095. https://doi.org/10.20944/preprints202403.1095.v1

Abstract

Colorectal cancer (CRC) with KRAS mutation is prone to develop metachronous metastasis. However, effective measures for prediction and prevention of such clinical issue are currently unavailable. In this study, we confirmed that KRAS mutation is a risk factor for CRC metachronous metastasis through meta-analysis and public database analysis. Based on the ICGC-AGRO database, we have constructed a risk scoring model for predicting metachronous metastasis in KRAS-mutant CRC using machine learning, which was validated in public datasets. Furthermore, we discovered that KRAS inhibitors can effectively suppress the migration and invasion capabilities of high risk CRC cells by wound healing assay and transwell experiment, which was validated ex vivo and in vivo using organoids and splenic liver metastatic mouse model. Finally, RNA sequencing, RT-qPCR, and western blots have proven that KRAS inhibitors can suppress the epithelial-mesenchymal transition (EMT) and transforming growth factor beta (TGF-beta) signaling pathway in CRC. Collectively, our study suggests that KRAS inhibitors may inhibit the metastatic ability of CRC by suppressing EMT and the TGF-beta pathway, suggesting their potential for the prevention of metachronous metastasis in CRC with KRAS mutation.

Keywords

KRAS inhibitor; metastasis; colorectal cancer; machine learning; meta analysis

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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