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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 40; pp. 12492 - 12497
• Main Authors: Park, Hansoo, Cho, Sung-Yup, Kim, Hyerim, Na, Deukchae, Han, Jee Yun, Chae, Jeesoo, Park, Changho, Park, Ok-Kyoung, Min, Seoyeon, Kang, Jinjoo, Choi, Boram, Min, Jimin, Kwon, Jee Young, Suh, Yun-Suhk, Kong, Seong-Ho, Lee, Hyuk-Joon, Liu, Edison T, Kim, Jong-Il, Kim, Sunghoon, Yang, Han-Kwang, Lee, Charles
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 06.10.2015; National Academy of Sciences
• Subjects: Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; bcl-X Protein - genetics; bcl-X Protein - metabolism; Biological Sciences; Cell Line, Tumor; Cell Survival - genetics; Comparative Genomic Hybridization; DNA Copy Number Variations; Exome - genetics; Female; Gastric cancer; Genome-Wide Association Study - methods; Genomics; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humans; Interleukin Receptor Common gamma Subunit - deficiency; Interleukin Receptor Common gamma Subunit - genetics; Male; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Mutation; RNA Interference; Sequence Analysis, DNA - methods; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Xenograft Model Antitumor Assays; copy number alteration; gastric cancer; patient-derived xenograft; whole-exome sequencing; druggable target
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1507491112

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.