Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

被引：297

作者：

Long, Georgina V. ^{[1
,2
,3
]}

Fung, Carina ^{[4
,5
]}

Menzies, Alexander M. ^{[1
,2
,6
]}

Pupo, Gulietta M. ^{[5
]}

Carlino, Matteo S. ^{[1
,5
,6
]}

Hyman, Jessica ^{[1
,7
,8
]}

Shahheydari, Hamideh ^{[4
,5
]}

Tembe, Varsha ^{[5
]}

Thompson, John F. ^{[1
,9
,10
,11
]}

Saw, Robyn P. ^{[1
,9
,10
,11
]}

Howle, Julie ^{[1
,9
,12
]}

Hayward, Nicholas K. ^{[13
]}

Johansson, Peter ^{[13
]}

Scolyer, Richard A. ^{[1
,7
,8
,14
]}

Kefford, Richard F. ^{[1
,2
,4
,5
]}

Rizos, Helen ^{[4
,5
]}

机构：

[1] Melanoma Inst Australia, Sydney, NSW 2060, Australia

[2] Univ Sydney, Sydney Med Sch, Discipline Med, Sydney, NSW 2006, Australia

[3] Mater Hosp, Sydney, NSW 2060, Australia

[4] Macquarie Univ, Australian Sch Adv Med, Precis Canc Therapy Lab, Sydney, NSW 2109, Australia

[5] Univ Sydney, Westmead Millennium Inst, Westmead Hosp, Westmead Inst Canc Res, Westmead, NSW 2145, Australia

[6] Westmead Hosp, Crown Princess Mary Canc Ctr, Dept Med Oncol, Westmead, NSW 2145, Australia

[7] Royal Prince Alfred Hosp, Dept Tissue Pathol, Camperdown, NSW 2006, Australia

[8] Royal Prince Alfred Hosp, Dept Diagnost Oncol, Camperdown, NSW 2006, Australia

[9] Univ Sydney, Sydney Med Sch, Discipline Surg, Sydney, NSW 2006, Australia

[10] Royal Prince Alfred Hosp, Dept Melanoma, Camperdown, NSW 2006, Australia

[11] Royal Prince Alfred Hosp, Dept Surg Oncol, Camperdown, NSW 2006, Australia

[12] Westmead Hosp, Crown Princess Mary Canc Ctr, Dept Surg Oncol, Westmead, NSW 2145, Australia

[13] QIMR Berghofer Med Res Inst, Oncogen Lab, Herston, Qld 4006, Australia

[14] Univ Sydney, Sydney Med Sch, Discipline Pathol, Sydney, NSW 2006, Australia

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

KINASE PATHWAY INHIBITION; ACQUIRED-RESISTANCE; MEK INHIBITORS; CONFERS RESISTANCE; TUMOR SUPPRESSORS; RAF INHIBITION; SOLID TUMORS; OPEN-LABEL; MUTATIONS; AMPLIFICATION;

D O I：

10.1038/ncomms6694

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：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF(V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2(C125S), but not the synonymous MEK1(C121S) protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.

引用

页数：9

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