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

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.

SUBMITTER: Park H

PROVIDER: S-EPMC4603466 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Park Hansoo H Cho Sung-Yup SY Kim Hyerim H Na Deukchae D Han Jee Yun JY Chae Jeesoo J Park Changho C Park Ok-Kyoung OK Min Seoyeon S Kang Jinjoo J Choi Boram B Min Jimin J Kwon Jee Young JY Suh Yun-Suhk YS Kong Seong-Ho SH Lee Hyuk-Joon HJ Liu Edison T ET Kim Jong-Il JI Kim Sunghoon S Yang Han-Kwang HK Lee Charles C

Proceedings of the National Academy of Sciences of the United States of America 20150923 40

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 ...[more]

PMID: 26401016

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Project description:Gastric cancer (GC) remains the second tumor caused death threat worldwide, and personalized medicine for GC is far from expectation. Finding novel, recurrently mutated genes through next-generation sequencing (NGS) is a powerful and productive approach. However, previous genomic data for GC are based on surgical resected samples while a large proportion of advanced gastric cancer (AGC) patients have already missed the chance for operation. The aim of this study is to assess frequent genomic alteration in AGC via biopsy samples. Here we performed targeted genomic sequencing of 78 AGC patients' tumor biopsies along with matched lymphocyte samples based on a 118 cancer related gene panel. In total, we observed 301 somatic nonsynonymous genomic alterations in 92 different genes, as well as 37 copy number gain events among 15 different genes (fold change 2-12), and validated the fold changes of ERBB2 copy number gains with IHC and FISH test showed an accuracy of 81.8%. Previously reported driver genes for gastric cancer (TP53, KMT2D, KMT2B, EGFR, PIK3CA, GNAQ, and ARID1A), and several unreported mutations (TGFBR2, RNF213, NF1, NSD1, and LRP2) showed high non-silent mutation prevalence (7.7%-34.6%). When comparing intestinal-type gastric cancer (IGC) with diffuse-type gastric cancer (DGC), TP53 and GNAQ appear to be more frequently mutated in IGC (P=0.028 and P=0.023, respectively), whereas LRP2, BRCA2 and FGFR3 mutations are not observed in IGC, but have 12.8%, 7.7% and 7.7% mutation rates, respectively, in DGC patients. Patients with one or more mutations in adherens junction pathway (CREBBP, EP300, CDH1, CTNNB1, EGFR, MET, TGFBR2 and ERBB2) or TGF-β signaling pathway (CREBBP, EP300, MYST4, KRAS and TGFBR2) showed significantly better overall survival (P=0.007 and P=0.014, respectively), consistent with The Cancer Genome Atlas (TCGA) cohort data. Importantly, 57 (73.1%) patients harbored at least one genomic alteration with potential treatments, making NGS-based drug target screening a viable option for AGC patients. Our study established a comprehensive genomic portrait of AGC, and identified several mutation signatures highly associated with clinical features, survival outcomes, which may be used to design future personalized treatments.

Project description:Background: The presence of heterogeneity and poor diagnosis in gastric adenocarcinoma poses a significant challenge to cancer treatment. To address the limited therapeutic options and enhance complex clinical management, we investigated the effects of targeting FOXO to inhibit CCKBR+ cancer cells in vitro and in vivo. Methods: We conducted single-cell sequencing (scRNA-seq) analysis on malignant epithelial cells from five gastric adenocarcinoma patients, revealing the notable heterogeneity within gastric adenocarcinoma (GA). We identified the oncological features of CCKBR+ tumors through immunohistochemistry and clinical statistical analysis. To validate the biological similarity of CCKBR+ tumors, we performed single-cell sequencing on datasets GSE183904 and TCGA. The mutational hallmarks of CCKBR+ tumors were detected using OncoDriveFML and GISTIC 2.0. To further investigate the potential target of CCKBR+ tumors, we utilized organoids and tumor xenograft mouse models, assessing the impact of FOXO inhibition. Finally, we employed CUT&Tag and flow cytometry to determine the genes regulated by FOXO in CCKBR+ tumors. Results: We identified a subset of CCKBR+ stem cell-like cancer cells associated with poorly differentiated features and a worse prognosis in gastric adenocarcinoma. This finding was validated through additional single-cell RNA sequencing (scRNA-seq), TCGA analysis, and histopathology, underscoring the heterogeneity of GA. The unique propensity for gene mutations, such as TP53, APC, SMAD4, and GLI3, was observed in CCKBR+ tumors. Mechanistically, our investigation revealed that FOXOs serve as key transcription factors in maintaining the homeostasis of CCKBR+ tumors. Inhibition of FOXO was found to suppress the growth of CCKBR+ organoids and xenograft tumors. Notably, FOXOs were identified as regulators of α2,3 sialylation levels in CCKBR+ tumor cells, shedding light on a crucial aspect of their homeostasis. Conclusions: CCKBR+ tumor cells significantly contribute to the intertumor heterogeneity of gastric cancer, leading to lower differentiation potential and a poorer prognosis. FOXO plays a crucial role in maintaining the homeostasis of CCKBR+ tumors by upregulating sialylation levels mediated by ST3GAL3/4/5 and ST6GALNAC6. Targeting FOXO effectively suppresses the progression of CCKBR+ tumors. This insight opens new avenues for developing targeted therapeutic strategies aimed at treating cancers associated with CCKBR, providing a novel perspective for precision medicine in this context.

Dataset Information

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

Publications

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

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