Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer.
de Rinaldis, E
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Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). Here, we describe an integrative genomic and RNAi-based approach that identifies and validates gene addictions in TNBCs. CNAs and gene expression alterations are integrated and genes scored for pre-specified target features revealing 130 candidate genes. We test functional dependence on each of these genes using RNAi in breast cancer and non-malignant cells, validating malignant cell selective dependence upon 37 of 130 genes. Further analysis reveals a cluster of 13 TNBC addiction genes frequently co-upregulated that includes genes regulating cell cycle checkpoints, DNA damage response, and malignant cell selective mitotic genes. We validate the mechanism of addiction to a potential drug target: the mitotic kinesin family member C1 (KIFC1/HSET), essential for successful bipolar division of centrosome-amplified malignant cells and develop a potential selection biomarker to identify patients with tumors exhibiting centrosome amplification.
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Cell Cycle Checkpoints
DNA Copy Number Variations
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Triple Negative Breast Neoplasms
Drug Target Discovery
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Nat Commun, 2018, 9 (1), pp. 1044 - ?