MEK1 mutations confer resistance to MEK and B-RAF inhibition

被引：514

作者：

Emery, Caroline M. ^{[1
,2
]}

Vijayendran, Krishna G. ^{[1
,2
]}

Zipser, Marie C. ^{[3
]}

Sawyer, Allison M. ^{[1
,2
]}

Niu, Lili ^{[1
,2
]}

Kim, Jessica J. ^{[1
,2
]}

Hatton, Charles ^{[1
,2
]}

Chopra, Rajiv ^{[4
]}

Oberholzer, Patrick A. ^{[1
,2
,3
,5
]}

Karpova, Maria B. ^{[3
]}

MacConaill, Laura E. ^{[1
,2
]}

Zhang, Jianming ^{[6
]}

Gray, Nathanael S. ^{[6
]}

Sellers, William R. ^{[4
]}

Dummer, Reinhard ^{[3
]}

Garraway, Levi A. ^{[1
,2
,5
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[3] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland

[4] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

[5] Broad Inst, Cambridge, MA 02142 USA

[6] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 48期

关键词：

BRAF; drug resistance; MAP kinase; melanoma; SMALL-CELL LUNG; PHASE-II; KINASE; CANCER; BRAF; GENE; IDENTIFICATION; SENSITIVITY; COMBINATION;

D O I：

10.1073/pnas.0905833106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Genetic alterations that activate the mitogen-activated protein kinase (MAP kinase) pathway occur commonly in cancer. For example, the majority of melanomas harbor mutations in the BRAF oncogene, which are predicted to confer enhanced sensitivity to pharmacologic MAP kinase inhibition (e. g., RAF or MEK inhibitors). We investigated the clinical relevance of MEK dependency in melanoma by massively parallel sequencing of resistant clones generated from a MEK1 random mutagenesis screen in vitro, as well as tumors obtained from relapsed patients following treatment with AZD6244, an allosteric MEK inhibitor. Most mutations conferring resistance to MEK inhibition in vitro populated the allosteric drug binding pocket or alpha-helix C and showed robust (approximate to 100-fold) resistance to allosteric MEK inhibition. Other mutations affected MEK1 codons located within or abutting the N-terminal negative regulatory helix (helix A), which also undergo gain-of-function germline mutations in cardio-facio-cutaneous (CFC) syndrome. One such mutation, MEK1(P124L), was identified in a resistant metastatic focus that emerged in a melanoma patient treated with AZD6244. Both MEK1(P124L) and MEK1(Q56P), which disrupts helix A, conferred cross-resistance to PLX4720, a selective B-RAF inhibitor. However, exposing BRAF-mutant melanoma cells to AZD6244 and PLX4720 in combination prevented emergence of resistant clones. These results affirm the importance of MEK dependency in BRAF-mutant melanoma and suggest novel mechanisms of resistance to MEK and B-RAF inhibitors that may have important clinical implications.

引用

页码：20411 / 20416

页数：6