Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts

被引：114

作者：

Kemper, Kristel ^{[1
]}

Krijgsman, Oscar ^{[1
]}

Cornelissen-Steijger, Paulien ^{[1
]}

Shahrabi, Aida ^{[1
]}

Weeber, Fleur ^{[1
]}

Song, Ji-Ying ^{[2
]}

Kuilman, Thomas ^{[1
]}

Vis, Daniel J. ^{[3
]}

Wessels, Lodewyk F. ^{[3
]}

Voest, Emile E. ^{[1
]}

Schumacher, Ton N. M. ^{[4
]}

Blank, Christian U. ^{[4
]}

Adams, David J. ^{[5
]}

Haanen, John B. ^{[4
]}

Peeper, Daniel S. ^{[1
]}

机构：

[1] Netherlands Canc Inst, Div Mol Oncol, Amsterdam, Netherlands

[2] Netherlands Canc Inst, Div Expt Anim Pathol, Amsterdam, Netherlands

[3] Netherlands Canc Inst, Computat Canc Biol, Amsterdam, Netherlands

[4] Netherlands Canc Inst, Div Immunol, Amsterdam, Netherlands

[5] Wellcome Trust Sanger Inst, Expt Canc Genet, Hinxton, Cambs, England

来源：

EMBO MOLECULAR MEDICINE | 2015年 / 7卷 / 09期

基金：

欧洲研究理事会; 英国惠康基金;

关键词：

Melanoma; drug resistance; tumor heterogeneity; patient-derived xenografts; ACQUIRED-RESISTANCE; PATHWAY ACTIVATION; BRAF INHIBITION; MEK INHIBITION; T790M MUTATION; EGFR; PREDISPOSES; MECHANISMS; EVOLUTION; BINARY;

D O I：

10.15252/emmm.201404914

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF(V600E) metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF(V600E), we identified a new activating insertion in MEK1. This MEK1(T55delinsRT) mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma.

引用

页码：1104 / 1118

页数：15

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