Uncovering synthetic lethal interactions for therapeutic targets and predictive markers in lung adenocarcinoma
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Jan-Gowth Chang1,*, Chia-Cheng Chen2,*, Yi-Ying Wu3,*, Ting-Fang Che4, Yi-Syuan Huang2, Kun-Tu Yeh5,6, Grace S. Shieh2,7,8, Pan-Chyr Yang4,9,10
1Department of Laboratory Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan
2Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
3Graduate Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
4Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
5Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
6Department of Pathology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
7Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
8Genome and Systems Biology Degree Program, Academia Sinica and National Taiwan University, Taipei, Taiwan
9Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan
10Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
*These authors have contributed equally to this work
Grace S. Shieh, email: [email protected]
Keywords: lung adenocarcinoma, TP53, prognosis marker, synthetic lethal, gene expression data
Received: March 18, 2016 Accepted: August 24, 2016 Published: September 15, 2016
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 platinum-based 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.
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