Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma

被引：146

作者：

Villanueva, Jessie ^{[1
]}

Infante, Jeffrey R. ^{[3
]}

Krepler, Clemens ^{[1
]}

Reyes-Uribe, Patricia ^{[1
]}

Samanta, Minu ^{[1
]}

Chen, Hsin-Yi ^{[1
]}

Li, Bin ^{[4
]}

Swoboda, Rolf K. ^{[1
]}

Wilson, Melissa ^{[5
]}

Vultur, Adina ^{[1
]}

Fukunaba-Kalabis, Mizuho ^{[1
]}

Wubbenhorst, Bradley ^{[4
]}

Chen, Thomas Y. ^{[1
]}

Liu, Qin ^{[1
]}

Sproesser, Katrin ^{[1
]}

DeMarini, Douglas J. ^{[8
]}

Gilmer, Tona M. ^{[9
]}

Martin, Anne-Marie ^{[8
]}

Marmorstein, Ronen ^{[2
]}

Schultz, David C. ^{[2
]}

Speicher, David W. ^{[1
]}

Karakousis, Giorgos C. ^{[5
,6
]}

Xu, Wei ^{[5
,6
]}

Amaravadi, Ravi K. ^{[5
,6
]}

Xu, Xiaowei ^{[6
,7
]}

Schuchter, Lynn M. ^{[5
,6
]}

Herlyn, Meenhard ^{[1
]}

Nathanson, Katherine L. ^{[4
,6
]}

机构：

[1] Wistar Inst Anat & Biol, Melanoma Res Ctr, Mol & Cellular Oncogenesis Program, Philadelphia, PA 19104 USA

[2] Wistar Inst Anat & Biol, Melanoma Res Ctr, Gene Express & Regulat Program, Philadelphia, PA 19104 USA

[3] Tennessee Oncol PLLC, Sarah Cannon Res Inst, Nashville, TN 37203 USA

[4] Univ Penn, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Dept Med, Div Hematol & Oncol, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[7] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[8] GlaxoSmithKline, Oncol Res & Dev, Collegeville, PA 19426 USA

[9] GlaxoSmithKline, Oncol Res & Dev, Res Triangle Pk, NC 27709 USA

来源：

CELL REPORTS | 2013年 / 4卷 / 06期

关键词：

DOSE-ESCALATION TRIAL; ACQUIRED-RESISTANCE; RAF INHIBITION; DRUG-RESISTANCE; UP-REGULATION; VEMURAFENIB; TRAMETINIB; OVERCOME;

D O I：

10.1016/j.celrep.2013.08.023

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.

引用

页码：1090 / 1099

页数：10

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