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

Authors
 Hyun Seok Kim  ;  Saurabh Mendiratta  ;  Jiyeon Kim  ;  Chad Victor Pecot  ;  Jill E. Larsen  ;  Iryna Zubovych  ;  Bo Yeun Seo  ;  Jimi Kim  ;  Banu Eskiocak  ;  Hannah Chung  ;  Elizabeth McMillan  ;  Sherry Wu  ;  Jef De Brabander  ;  Kakajan Komurov  ;  Jason E. Toombs  ;  Shuguang Wei  ;  Michael Peyton  ;  Noelle Williams  ;  Adi F. Gazdar  ;  Bruce A. Posner  ;  Rolf Brekken  ;  Anil K. Sood  ;  Ralph J. Deberardinis  ;  Michael G. Roth  ;  John D. Minna  ;  Michael A. White 
Citation
 CELL, Vol.155(3) : 552-566, 2013 
Journal Title
CELL
ISSN
 0092-8674 
Issue Date
2013
MeSH
Animals ; CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Carcinoma, Non-Small-Cell Lung/pathology ; Carrier Proteins ; Cell Line, Tumor ; Coatomer Protein/metabolism ; Drug Screening Assays, Antitumor* ; Female ; Genes, ras ; Heterografts ; Humans ; Indoles/pharmacology* ; Lung Neoplasms/metabolism* ; Lung Neoplasms/pathology ; Lysosomes/metabolism ; Mice ; Molecular Targeted Therapy ; NLR Family, Pyrin Domain-Containing 3 Protein ; Neoplasm Transplantation ; Oxidative Phosphorylation ; Triazines/pharmacology*
Keywords
Animals ; CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Carcinoma, Non-Small-Cell Lung/pathology ; Carrier Proteins ; Cell Line, Tumor ; Coatomer Protein/metabolism ; Drug Screening Assays, Antitumor* ; Female ; Genes, ras ; Heterografts ; Humans ; Indoles/pharmacology* ; Lung Neoplasms/metabolism* ; Lung Neoplasms/pathology ; Lysosomes/metabolism ; Mice ; Molecular Targeted Therapy ; NLR Family, Pyrin Domain-Containing 3 Protein ; Neoplasm Transplantation ; Oxidative Phosphorylation ; Triazines/pharmacology*
Abstract
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-occuring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a 7-gene expression signature. Target efficacies were validated in vivo, and mechanism of action studies uncovered new cancer cell biology.
Files in This Item:
T201305745.pdf Download
DOI
10.1016/j.cell.2013.09.041
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/89206
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