Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers

被引：0

作者：

Georgia Hatzivassiliou

Jacob R. Haling

Huifen Chen

Kyung Song

Steve Price

Robert Heald

Joanne F. M. Hewitt

Mark Zak

Ariana Peck

Christine Orr

Mark Merchant

Klaus P. Hoeflich

Jocelyn Chan

Shiuh-Ming Luoh

Daniel J. Anderson

Mary J. C. Ludlam

Christian Wiesmann

Mark Ultsch

Lori S. Friedman

Shiva Malek

Marcia Belvin

机构：

[1] Genentech,Department of Translational Oncology

[2] Inc.,Department of Biochemical and Cellular Pharmacology

[3] 1 DNA Way,Department of Discovery Chemistry

[4] South San Francisco,Department of Discovery Oncology

[5] California 94080,Department of Structural Biology

[6] USA,undefined

[7] Genentech,undefined

[8] Inc.,undefined

[9] 1 DNA Way,undefined

[10] South San Francisco,undefined

[11] California 94080,undefined

[12] USA,undefined

[13] Genentech,undefined

[14] Inc.,undefined

[15] 1 DNA Way,undefined

[16] South San Francisco,undefined

[17] California 94080,undefined

[18] USA,undefined

[19] Argenta,undefined

[20] 8/9 Spire Green Centre,undefined

[21] Flex Meadow,undefined

[22] Harlow,undefined

[23] Essex CM19 5TR,undefined

[24] UK,undefined

[25] Genentech,undefined

[26] Inc.,undefined

[27] 1 DNA Way,undefined

[28] South San Francisco,undefined

[29] California 94080,undefined

[30] USA,undefined

[31] Genentech,undefined

[32] Inc.,undefined

[33] 1 DNA Way,undefined

[34] South San Francisco,undefined

[35] California 94080,undefined

[36] USA,undefined

[37] Present addresses: WestCHEM,undefined

[38] School of Chemistry,undefined

[39] University of Glasgow,undefined

[40] Joseph Black Building,undefined

[41] University Avenue,undefined

[42] Glasgow G12 8QQ,undefined

[43] UK (J.F.M.H.); MRC Mitochondrial Biology Unit,undefined

[44] Wellcome Trust/MRC Building,undefined

[45] Hills Road,undefined

[46] Cambridge CB2 OXY,undefined

[47] UK (A.P.); Novartis Institutes for Biomedical Research,undefined

[48] Fabrikstrasse 16,undefined

[49] CH-4002 Basel,undefined

[50] Switzerland (C.W.); Cairn Biosciences Inc.,undefined

来源：

Nature | 2013年 / 501卷

关键词：

D O I：

暂无

中图分类号：

学科分类号：

摘要：

The mechanism of action of three different allosteric MEK inhibitors that target the MAP kinase pathway is investigated, and their efficacy is shown to be explained by the distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours; this work provides a rationale for designing more effective cancer therapies for these common genetic subtypes of cancer.

引用

页码：232 / 236

页数：4

共 40 条

[31] PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells
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[32] BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition
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[33] Pan-cancer efficacy of BRAF and/or MEK inhibitors in BRAF V600-mutant multiple non-melanoma cancers: A clinico-genomic study.
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[35] A phase I trial combining MEK-1/2 inhibition in combination with 5-fluorouracil and radiation for KRAS, BRAF, and NRAS mutant locally advanced rectal adenocarcinoma
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[37] The novel pan-RAF-MEK glue NST-628 is highly efficacious as monotherapy and as an anchor for vertical inhibition of the RAS-MAPK pathway in KRAS-mutant cancers
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[38] The role of JAK1/2-STAT3 as acute resistance mechanism to MEK inhibition in BRAF-mutant colorectal cancer cell lines.
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[39] Failure to Induce Apoptosis via BCL-2 Family Proteins Underlies Lack of Efficacy of Combined MEK and PI3K Inhibitors for KRAS-Mutant Lung Cancers
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[40] Oncogenic mutant KRAS modulates EZH2 expression through MEK-ERK and PI3K/AKT signaling in NSCLC: differential effects of different KRAS mutations and increased efficacy of inhibition combined with EZH2 targeted therapy
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