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Development of small-molecule therapeutics and strategies for targeting RAF kinase in BRAF-mutant colorectal cancer

Authors Pan JH, Zhou H, Zhu SB, Huang JL, Zhao XX, Ding H, Pan YL

Received 4 April 2018

Accepted for publication 16 May 2018

Published 1 August 2018 Volume 2018:10 Pages 2289—2301

DOI https://doi.org/10.2147/CMAR.S170105

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Editor who approved publication: Professor Nakshatri


Jing-hua Pan,1 Hong Zhou,2 Sheng-bin Zhu,1 Jin-lian Huang,1 Xiao-xu Zhao,1 Hui Ding,1 Yun-long Pan1

1Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China; 2Department of Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China

Abstract: RAF kinase is crucially involved in cell proliferation and survival in colorectal cancer (CRC). Patients with metastatic CRC (mCRC) harboring BRAF mutations (BRAFms) not only experience a poor prognosis but also benefit less from therapeutics targeting ERK signaling. With advances in RAF inhibitors and second-generation inhibitors including encorafenib and vemurafenib, which have been approved for treating BRAF-V600E malignancies, the combinatorial therapeutic strategies of RAF inhibitors elicit remarkable responses in patients with BRAF-V600E mCRC. However, the therapeutic efficacy is restricted by resistance, which might be due to RAF dimerization and reactivation of the MAPK pathway. In addition, the next-generation RAF inhibitors, which are characterized by varying structural and biochemical properties, have achieved preclinical and clinical advances. Herein, we summarize the existing mechanism of RAF kinases in CRC, including MAPK feedback reactivation of resistance to RAF inhibitors. We additionally summarize the development of three generations of RAF inhibitors and different therapeutic strategies including the combination of EGFR, BRAF, and PI3K inhibitors for BRAFm CRC treatment.

Keywords: BRAF, inhibitor, colorectal cancer, V600E, structure, resistance

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