American Association for Cancer Research
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00085472can082627-sup-can-08-2627r_supplementary_table_legends_1-2.pdf (9.53 kB)

Supplementary Table Legends 1-2 from Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy

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posted on 2023-03-30, 19:09 authored by Sherif Daouti, Huisheng Wang, Wen-hui Li, Brian Higgins, Kenneth Kolinsky, Kathryn Packman, Anthony Specian, Norman Kong, Nicholas Huby, Yang Wen, Qing Xiang, Frank J. Podlaski, Yang He, Nader Fotouhi, David Heimbrook, Huifeng Niu
Supplementary Table Legends 1-2 from Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy

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ARTICLE ABSTRACT

The mitogen-activated protein kinase (MAPK) signal transduction pathway plays a central role in regulating tumor cell growth, survival, differentiation, and angiogenesis. The key components of the Ras/Raf/MEK/ERK signal module are frequently altered in human cancers. Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive. Here, we report a potent and highly selective non–ATP-competitive MEK1/2 inhibitor, RO4927350, with a novel chemical structure and unique mechanism of action. It selectively blocks the MAPK pathway signaling both in vitro and in vivo, which results in significant antitumor efficacy in a broad spectrum of tumor models. Compared with previously reported MEK inhibitors, RO4927350 inhibits not only ERK1/2 but also MEK1/2 phosphorylation. In cancer cells, high basal levels of phospho-MEK1/2 rather than phospho-ERK1/2 seem to correlate with greater sensitivity to RO4927350. Furthermore, RO4927350 prevents a feedback increase in MEK phosphorylation, which has been observed with other MEK inhibitors. We show that B-Raf rather than C-Raf plays a critical role in the feedback regulation. The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation. [Cancer Res 2009;69(5):1924–32

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