Integrated genomics and functional validation
identiﬁes malignant cell speciﬁc dependencies in
triple negative breast cancer
, Daniel Weekes
, Konstantinos Drosopoulos
, Patrycja Gazinska
, Elodie Noel
, Hasan Mirza
, Jelmar Quist
, Fara Brasó-Maristany
, Sumi Mathew
, Riccardo Ferro
Ana Mendes Pereira
, Cynthia Prince
, Farzana Noor
, Erika Francesch-Domenech
, Rebecca Marlow
Emanuele de Rinaldis
, Anita Grigoriadis
, Spiros Linardopoulos
, Pierfrancesco Marra
Andrew N.J. Tutt
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 check-
points, 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
Breast Cancer Now Research Unit, King’s College London, London SE1 9RT, UK.
School of Cancer and Pharmaceutical Sciences, King’s Health Partners
AHSC, Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK.
The Breast Cancer Now Toby Robins Research Centre, The
Institute of Cancer Research, London SW7 3RP, UK.
Cancer Bioinformatics, King’s College London, London SE1 9RT, UK.
Precision Immunology Cluster,
Sanoﬁ, 640 Memorial Drive, Cambridge, MA 02149, USA.
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2
5NG, UK. These contributed equally: Pierfrancesco Marra, Andrew N. J. Tutt. Correspondence and requests for materials should be addressed to
A.N.J.T. (email: email@example.com)