|Title:||Uncovering synthetic lethal interactions for therapeutic targets and predictive markers in lung adenocarcinoma||Authors:||Chang J.-G.
|Keywords:||Gene expression data; Lung adenocarcinoma; Prognosis marker; Synthetic lethal; TP53||Issue Date:||2016||Publisher:||Impact Journals LLC||Journal Volume:||7||Journal Issue:||45||Start page/Pages:||73664-73680||Source:||Oncotarget||Abstract:||
Two genes are called synthetic lethal (SL) if their simultaneous mutation leads to cell death, but mutation of either individual does not. Targeting SL partners of mutated cancer genes can selectively kill cancer cells, but leave normal cells intact. We present an integrated approach to uncover SL gene pairs as novel therapeutic targets of lung adenocarcinoma (LADC). Of 24 predicted SL pairs, PARP1-TP53 was validated by RNAi knockdown to have synergistic toxicity in H1975 and invasive CL1-5 LADC cells; additionally FEN1-RAD54B, BRCA1-TP53, BRCA2-TP53 and RB1- TP53 were consistent with the literature. While metastasis remains a bottleneck in cancer treatment and inhibitors of PARP1 have been developed, this result may have therapeutic potential for LADC, in which TP53 is commonly mutated. We also demonstrated that silencing PARP1 enhanced the cell death induced by the platinumbased chemotherapy drug carboplatin in lung cancer cells (CL1-5 and H1975). IHC of RAD54B↑, BRCA1↓-RAD54B↑, FEN1(N)↑-RAD54B↑ and PARP1↑-RAD54B↑ were shown to be prognostic markers for 131 Asian LADC patients, and all markers except BRCA1↓- RAD54B↑ were further confirmed by three independent gene expression data sets (a total of 426 patients) including The Cancer Genome Atlas (TCGA) cohort of LADC. Importantly, we identified POLB-TP53 and POLB as predictive markers for the TCGA cohort (230 subjects), independent of age and stage. Thus, POLB and POLB-TP53 may be used to stratify future non-Asian LADC patients for therapeutic strategies.
|ISSN:||1949-2553||DOI:||10.18632/oncotarget.12046||SDG/Keyword:||carboplatin; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; tumor marker; aged; Article; cancer chemotherapy; cancer prognosis; cohort analysis; controlled study; female; FEN1 gene; gene; gene expression profiling; gene identification; gene silencing; genetic association; human; human cell; human tissue; lung adenocarcinoma; major clinical study; male; PARP1 gene; POLB gene; RAD54B gene; RB1 gene; RNA interference; SL gene; tissue microarray; tumor suppressor gene; adenocarcinoma; cell survival; epistasis; gene expression; gene expression profiling; genetics; immunohistochemistry; lethal mutation; lung tumor; metabolism; mortality; pathology; prognosis; proportional hazards model; reproducibility; Adenocarcinoma; Biomarkers, Tumor; Cell Survival; Epistasis, Genetic; Gene Expression; Gene Expression Profiling; Genes, p53; Humans; Immunohistochemistry; Lung Neoplasms; Poly (ADP-Ribose) Polymerase-1; Prognosis; Proportional Hazards Models; Reproducibility of Results; RNA Interference; Synthetic Lethal Mutations
|Appears in Collections:||醫學系|
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