[Background]Recent advances in high throughput analysis of genetic and epigenetic alterations revealed numerous changes in lung cancer cells. It is vital to sort out genes that substantially contribute to oncogenic properties of cancer cells from these numerous altered genes by performing a functional screening because such genes could serve as valuable therapeutic targets. To this end, we performed a screening with a pooled shRNA library for genes critical for survival and/or proliferation in lung cancer cells. [Methods and Results]A pooled shRNA library comprising 5,000 genes, with 3 to 7 constructs per gene, were transduced in NCI-H460 lung cancer cell line. Subsequently, genomic DNA was extracted from the transduced cells and numbers of shRNA for each gene were quantified by next generation sequencing. Through a stringent filtering process we narrowed down genes to a list of 24 candidates as potentially target genes. Next, we integrated data of genome-wild gene expression and copy number analyses of a panel of lung cancer cell lines to narrow down to genes more relevant to lung cancer. Through these processes, we listed up several candidate genes. Among them, we focused on Cytochrome c oxidase subunit 5a (COX5A), one of the nuclear encoded subunits of cytochrome c oxidase, the terminal protein of the mitochondrial electron transport chain. Importantly, COX5A knockdown didn't suppress growth of HBEC3, a normal control cell line, suggesting that therapeutics of targeting COX5A may have high therapeutic index.

[Conclusions]Our results suggest that inhibiting COX5A may be an attractive strategy for the treatment of NSCLC with high therapeutic index.

Citation Format: Toshio Kato, Mitsuo Sato, Masashi Kondo, Tomohiko Kakumu, Naoyuki Yogo, Tetsunari Hase, Masahiro Morise, Yoshionori Hasegawa, John D. Minnna, Luc Girard. Cytochrome c oxidase subunit 5a (COX5A) is identified as a potential therapeutic target for lung cancer with high therapeutic index through a pooled shRNA screen. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 206.