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 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.
Highlights
Lung cancer is the most common cancer worldwide in terms of both incidence and mortality [1]
By screening across these synthetic lethal (SL) pairs using microarray gene expression data of various cancerous and non-cancerous tissues, we found that some gene pairs, e.g., FEN1-RAD54B, were simultaneously differentially expressed in high fractions of several cancerous tissues including lung adenocarcinoma (LADC)
This was consistent with the finding that co-expression of gene pairs was a relevant feature for predicting genetic interactions genome-wide in S. cerevisiae and C. elegans [6, 8, 9]
Summary
Lung cancer is the most common cancer worldwide in terms of both incidence and mortality [1]. Most cases of adenocarcinoma are associated with smoking, but among never-smokers, adenocarcinoma is the most common subtype of lung cancer. Multiple genes are mutated during tumorigenesis, with those contributing to tumor formation and growth are called cancer genes [2]. Cancer genes www.impactjournals.com/oncotarget can be categorized into oncogenes, tumor suppressor genes and stability genes. Mutant oncogenes and tumor suppressor genes drive cancer cell proliferation while stability genes are involved in maintenance of genome integrity. To date some therapeutics directed against oncogenes have led to increases in patient survival, many fail due to intrinsic or adaptive resistance of the cancer cell population to the therapeutics. In lung adenocarcinoma, efficacy of EGFR-inhibition is reduced by downstream KRAS-activating mutation [3]
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