Chang Jan-Gowth, Chen Chia-Cheng, Wu Yi-Ying, Che Ting-Fang, Huang Yi-Syuan, Yeh Kun-Tu, Shieh Grace S, Yang Pan-Chyr
Department of Laboratory Medicine and Epigenome Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan.
Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
Oncotarget. 2016 Nov 8;7(45):73664-73680. doi: 10.18632/oncotarget.12046.
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.
如果两个基因同时发生突变会导致细胞死亡，但单个基因发生突变则不会，那么这两个基因被称为合成致死（SL）基因。靶向突变的癌症基因的SL伙伴可以选择性地杀死癌细胞，而使正常细胞保持完整。我们提出了一种综合方法来发现SL基因对，作为肺腺癌（LADC）的新型治疗靶点。在24对预测的SL基因对中，PARP1 - TP53通过RNA干扰敲低在H1975和侵袭性CL1 - 5 LADC细胞中被验证具有协同毒性；此外，FEN1 - RAD54B、BRCA1 - TP53、BRCA2 - TP53和RB1 - TP53与文献报道一致。虽然转移仍然是癌症治疗的一个瓶颈，并且已经开发出PARP1抑制剂，但这一结果可能对TP53通常发生突变的LADC具有治疗潜力。我们还证明，沉默PARP1可增强铂类化疗药物卡铂在肺癌细胞（CL1 - 5和H1975）中诱导的细胞死亡。RAD54B↑、BRCA1↓ - RAD54B↑、FEN1(N)↑ - RAD54B↑和PARP1↑ - RAD54B↑的免疫组化结果显示为131例亚洲LADC患者的预后标志物，除BRCA1↓ - RAD54B↑外，所有标志物均通过包括癌症基因组图谱（TCGA）LADC队列在内的三个独立基因表达数据集（共426例患者）进一步得到证实。重要的是，我们确定POLB - TP53和POLB是TCGA队列（230名受试者）的预测标志物，与年龄和分期无关。因此，POLB和POLB - TP53可用于对未来非亚洲LADC患者进行治疗策略分层。
