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Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer
- Genomic alterations in BCL2L1 and DLC1 contribute to drug sensitivity in gastric cancer
- Park; H.; Cho; S.-Y.; Kim; Na; D.; Han; J.Y.; Chae; J.; C.; O.-K.; Min; S.; Kang; Choi; B.; Kwon; Suh; Y.-S.; Kong; S.-H.; Lee; H.-J.; Liu; E.T.; J.-I.; Yang; H.-K.
- Ewha Authors
- Charles Lee; 박한수; 조성엽
- SCOPUS Author ID
- Charles Lee; 박한수; 조성엽
- Issue Date
- Journal Title
- Proceedings of the National Academy of Sciences of the United States of America
- Proceedings of the National Academy of Sciences of the United States of America vol. 112, no. 40, pp. 12492 - 12497
- Gastric cancer; copy number alteration; whole-exome sequencing; Patient-derived xenograft; druggable target
- National Academy of Sciences
- SCI; SCIE; SCOPUS
- Document Type
- 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.
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