Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer

Nirmesh Patel ,Patrycja Gazinska ,Spiros Linardopoulos ,Jelmar Quist ,Rebecca Marlow ,Farzana Noor ,Mamun Rashid ,Sunil Mathew ,Elodie Noël ,Cynthia Prince ,Konstantinos Drosopoulos ,Hasan Mirza ,Fara Brasó-Maristany ,Pierfrancesco Marra ,Riccardo Ferro ,Emanuele De Rinaldis ,Daniel Weekes ,Anita Grigoriadis ,Erika Francesch-Domenech ,Ana M Mendes-Pereira ,Andrew Tutt

doi:10.1038/s41467-018-03283-z

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.

Highlights

Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs)
Recurrent across external data sets, we focus on a potential drug target the kinesin family member C1 (KIFC1/HSET) and show that KIFC1 is a selective essential gene for many malignant breast cancer cells, demonstrating the mechanism of addiction to be based upon clustering of abnormal multiple centrosomes relevant to the majority of TNBCs that have centrosome amplification[13]
All the above data were collated in the Target ID data platform that was used as a foundation for the application of a pre-specified selection algorithm for putative addiction genes in TNBC

Summary

Introduction

Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). 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. Recurrent across external data sets, we focus on a potential drug target the kinesin family member C1 (KIFC1/HSET) and show that KIFC1 is a selective essential gene for many malignant breast cancer cells, demonstrating the mechanism of addiction to be based upon clustering of abnormal multiple centrosomes relevant to the majority of TNBCs that have centrosome amplification[13]. We developed a potential centrosome abnormality biomarker applicable to routinely fixed paraffin-embedded tumor tissue to enable patient segmentation of those with cancers susceptible to KIFC1/centrosome amplification targeted therapy

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