Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer.
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Authors
Patel, N
Weekes, D
Drosopoulos, K
Gazinska, P
Noel, E
Rashid, M
Mirza, H
Quist, J
Brasó-Maristany, F
Mathew, S
Ferro, R
Pereira, AM
Prince, C
Noor, F
Francesch-Domenech, E
Marlow, R
de Rinaldis, E
Grigoriadis, A
Linardopoulos, S
Marra, P
Tutt, ANJ
Weekes, D
Drosopoulos, K
Gazinska, P
Noel, E
Rashid, M
Mirza, H
Quist, J
Brasó-Maristany, F
Mathew, S
Ferro, R
Pereira, AM
Prince, C
Noor, F
Francesch-Domenech, E
Marlow, R
de Rinaldis, E
Grigoriadis, A
Linardopoulos, S
Marra, P
Tutt, ANJ
Document Type
Journal Article
Date
2018-03-13
Date Accepted
2018-02-01
Abstract
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.
Citation
Nature communications, 2018, 9 (1), pp. 1044 - ?
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
2041-1723
eISSN
2041-1723
Collections
Research Team
Drug Target Discovery