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Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer
Cancer Discovery ( IF 28.2 ) Pub Date : 2018-04-01 , DOI: 10.1158/2159-8290.cd-17-1227
Mehlika Hazar-Rethinam , Marianna Kleyman , G. Celine Han , David Liu , Leanne G. Ahronian , Heather A. Shahzade , Lifeng Chen , Aparna R. Parikh , Jill N. Allen , Jeffrey W. Clark , Eunice L. Kwak , Jason E. Faris , Janet E. Murphy , Theodore S. Hong , Emily E. Van Seventer , Brandon Nadres , Catriona B. Hong , Joseph M. Gurski , Nicholas A. Jessop , Dora Dias-Santagata , A. John Iafrate , Eliezer M. Van Allen , Ryan B. Corcoran

Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAFV600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo. In vitro, the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo. Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome.

Significance: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAFV600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417–27. ©2018 AACR.

See related commentary by Janku, p. 389.

See related article by Corcoran et al., p. 428.

This article is highlighted in the In This Issue feature, p. 371



中文翻译:

克服BRAF V600E大肠癌获得性耐药的异质性的融合治疗策略

与获得性耐药相关的克隆异质性提出了关键的治疗挑战。来自接受BRAF抑制剂组合的BRAF V600E大肠癌患者的配对肿瘤活检的全基因组测序和无细胞DNA(cfDNA)的靶向测序,确定了驱动获得性耐药的MAPK途径组分中有14种不同的改变,其中多达8种改变单身患者。我们开发了一个集合克隆系统,以研究在体外体内获得性耐药期间的克隆生长。体外,可以在治疗期间从培养基中分离的cfDNA中实时监测各个耐药克隆的动态。在使用BRAF,EGFR和MEK抑制剂治疗期间,观察到多个耐药克隆的生长。然而,ERK抑制,特别是与BRAF和EGFR抑制的组合,在体外体内显着消除了克隆的生长。因此,融合的前期治疗可以抑制具有临床观察到的耐药性改变的异质克隆的生长,这可以改善临床结果。

启示:我们观察到BRAF V600E结直肠癌中MAPK途径的异质性,反复性改变是获得性耐药的关键驱动力,个别患者可检测到多个同时发生的耐药性改变。使用新型的池克隆系统,我们确定能够拦截多种抗性机制作为抑制获得性抗性出现的潜在方法的聚合前期治疗策略。巨蟹座Discov; 8(4); 417–27。©2018 AACR。

参见Janku,p。的相关评论。389

参见Corcoran等人的相关文章,第1页。428

本文在本期功能中突出显示。371

更新日期:2018-04-02
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