Systematic Identification of Molecular Subtype-Selective Vulnerabilities in Non-Small-Cell Lung Cancer

被引:153
作者
Kim, Hyun Seok [1 ]
Mendiratta, Saurabh [1 ]
Kim, Jiyeon [2 ]
Pecot, Chad Victor [5 ]
Larsen, Jill E. [3 ]
Zubovych, Iryna [4 ]
Seo, Bo Yeun [1 ]
Kim, Jimi [1 ]
Eskiocak, Banu [1 ]
Chung, Hannah [1 ]
McMillan, Elizabeth [1 ]
Wu, Sherry [5 ]
De Brabander, Jef [4 ]
Komurov, Kakajan [7 ]
Toombs, Jason E. [3 ]
Wei, Shuguang [4 ]
Peyton, Michael [3 ]
Williams, Noelle [4 ]
Gazdar, Adi F. [3 ]
Posner, Bruce A. [4 ]
Brekken, Rolf A. [3 ]
Sood, Anil K. [6 ]
Deberardinis, Ralph J. [2 ]
Roth, Michael G. [4 ]
Minna, John D. [3 ]
White, Michael A. [1 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Childrens Med Ctr, Res Inst, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA
[4] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA
[5] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Houston, TX 77030 USA
[6] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77030 USA
[7] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA
关键词
PROTEIN; APOPTOSIS; GENE; INFLAMMASOMES; RIPOPTOSOME; INHIBITORS; ASSEMBLES; COATOMER; SURVIVAL; PLATFORM;
D O I
10.1016/j.cell.2013.09.041
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Context-specific molecular vulnerabilities that arise during tumor evolution represent an attractive intervention target class. However, the frequency and diversity of somatic lesions detected among lung tumors can confound efforts to identify these targets. To confront this challenge, we have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%-16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature. Target efficacies were validated in vivo, and mechanism-of-action studies informed generalizable principles underpinning cancer cell biology.
引用
收藏
页码:552 / 566
页数:15
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