Concurrent Targeting of KRAS and AKT by MiR-4689 Is a Novel Treatment Against Mutant KRAS Colorectal Cancer.

Masaki Mori,Taishi Hata,Yusuke Takahashi,Yuichiro Doki,Junichi Nishimura,Ichiro Takemasa,Naohiro Nishida,Masayuki Hiraki,Tsunekazu Mizushima,Masaaki Miyo,Jae-Won Soh,Mamoru Uemura,Hirofumi Yamamoto,Xin Wu,Hidekazu Takahashi

doi:10.1038/mtna.2015.5

Masaki Mori, Taishi Hata

Open Access

https://doi.org/10.1038/mtna.2015.5

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Abstract

KRAS mutations are a major cause of drug resistance to molecular-targeted therapies. Aberrant epidermal growth factor receptor (EGFR) signaling may cause dysregulation of microRNA (miRNA) and gene regulatory networks, which leads to cancer initiation and progression. To address the functional relevance of miRNAs in mutant KRAS cancers, we transfected exogenous KRASG12V into human embryonic kidney 293 and MRC5 cells with wild-type KRAS and BRAF genes, and we comprehensively profiled the dysregulated miRNAs. The result showed that mature miRNA oligonucleotide (miR)-4689, one of the significantly down-regulated miRNAs in KRASG12V overexpressed cells, was found to exhibit a potent growth-inhibitory and proapoptotic effect both in vitro and in vivo. miR-4689 expression was significantly down-regulated in cancer tissues compared to normal mucosa, and it was particularly decreased in mutant KRAS CRC tissues. miR-4689 directly targets v-ki-ras2 kirsten rat sarcoma viral oncogene homolog (KRAS) and v-akt murine thymoma viral oncogene homolog 1(AKT1), key components of two major branches in EGFR pathway, suggesting KRAS overdrives this signaling pathway through inhibition of miR-4689. Overall, this study provided additional evidence that mutant KRAS functions as a broad regulator of the EGFR signaling cascade by inhibiting miR-4689, which negatively regulates both RAS/mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways. These activities indicated that miR-4689 may be a promising therapeutic agent in mutant KRAS CRC.

Highlights

Recent advances in our comprehension of the specific signaling pathways in cancer cells have offered novel targeted therapies for patients with metastatic colorectal cancer
A retrospective analysis of randomized, phase 2 OPUS and phase 3 CRYSTAL clinical trials revealed that cetuximab combined with a first-line chemotherapy (FOLFOX4 or FOLFIRI) significantly improved the prognosis of patients with wild-type KRAS metastatic colorectal cancer (mCRC) compared to chemotherapy alone
This blocking leads to the inhibition of epidermal growth factor receptors (EGFRs) downstream signaling pathways, including the rapidly accelerated fibrosarcoma (RAF)/MEK/extracellular signal-regulated kinase (ERK) pathway, which is mainly involved in cell proliferation, and the phosphoinositide 3-kinase (PI3K)/AKT pathway, which is mainly involved in cell survival and tumor invasion.[8,9]

Summary

Introduction

Recent advances in our comprehension of the specific signaling pathways in cancer cells have offered novel targeted therapies for patients with metastatic colorectal cancer (mCRC). Studies have shown that monoclonal antibodies that target epidermal growth factor receptors (EGFRs) provide a survival benefit in mCRCs that harbor wild-type KRAS.[1,2] A retrospective analysis of randomized, phase 2 OPUS and phase 3 CRYSTAL clinical trials revealed that cetuximab combined with a first-line chemotherapy (FOLFOX4 or FOLFIRI) significantly improved the prognosis of patients with wild-type KRAS mCRC compared to chemotherapy alone These effects were not observed in patients with mutant KRAS mCRC.[2,3] Because KRAS mutations occur in ~40% of patients with mCRC,[4] novel therapeutic strategies are urgently needed for treating this population. This constitutive activity is considered the major reason that mutant KRAS CRCs are resistant to anti-EGFR therapy.[1,7]

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