View : 227 Download: 0

Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer

Title
Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer
Authors
ParkH.ChoS.-Y.KimNaD.HanJ.Y.ChaeJ.C.O.-K.MinS.KangChoiB.KwonSuhY.-S.KongS.-H.LeeH.-J.LiuE.T.J.-I.YangH.-K.
Ewha Authors
Charles Lee박한수조성엽
SCOPUS Author ID
Charles Leescopus; 박한수scopus; 조성엽scopus
Issue Date
2015
Journal Title
Proceedings of the National Academy of Sciences of the United States of America
ISSN
0027-8424JCR Link
Citation
vol. 112, no. 40, pp. 12492 - 12497
Keywords
Gastric cancercopy number alterationwhole-exome sequencingPatient-derived xenograftdruggable target
Publisher
National Academy of Sciences
Indexed
SCI; SCIE; SCOPUS scopus
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Recent high-throughput analyses of genomic alterations revealed several driver genes and altered pathways in GC. However, therapeutic applications from genomic data are limited, largely as a result of the lack of druggable molecular targets and preclinical models for drug selection. To identify new therapeutic targets for GC, we performed array comparative genomic hybridization (aCGH) of DNA from 103 patients with GC for copy number alteration (CNA) analysis, and whole-exome sequencing from 55 GCs from the same patients for mutation profiling. Pathway analysis showed recurrent alterations in the Wnt signaling [APC, CTNNB1, and DLC1 (deleted in liver cancer 1)], ErbB signaling (ERBB2, PIK3CA, and KRAS), and p53 signaling/apoptosis [TP53 and BCL2L1 (BCL2-like 1)] pathways. In 18.4% of GC cases (19/103), amplification of the antiapoptotic gene BCL2L1 was observed, and subsequently a BCL2L1 inhibitor was shown to markedly decrease cell viability in BCL2L1-amplified cell lines and in similarly altered patient-derived GC xenografts, especially when combined with other chemotherapeutic agents. In 10.9% of cases (6/55), mutations in DLC1 were found and were also shown to confer a growth advantage for these cells via activation of Rho-ROCK signaling, rendering these cells more susceptible to a ROCK inhibitor. Taken together, our study implicates BCL2L1 and DLC1 as potential druggable targets for specific subsets of GC cases.
DOI
10.1073/pnas.1507491112
Appears in Collections:
일반대학원 > 생명과학과 > Journal papers
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML


qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE