LB45
Identification of potential therapeutic targets in HER2 amplified breast carcinomas by integrative molecular profiling
K.K. Shiu1, H.M. Horlings2, A. Mackay1, R. Natrajan1, M.B. Lambros1, F. Reyal3, P. Kristel3, M. van de Vijver2, N. Turner1, A. Ashworth1, C.J. Lord1, J.S. Reis-Filho1
1Breakthrough Breast Cancer Research Centre, London, UK; 2Academic Medical Center, Amsterdam, Netherlands; 3Netherlands Cancer Institute, Amsterdam, Netherlands
Background
HER2 positive breast cancers comprise a heterogeneous group of aggressive
tumours, which can be targeted with Trastuzumab and Lapatinib. Although
anti-HER2 targeted therapies have been shown to increase the survival of
patients with HER2 positive cancer, de novo and acquired resistance to
these agents is not uncommon. Therefore, identification of additional
therapeutic targets could help refine the treatment of HER2 positive patients.
There is evidence to suggest that genes whose expression correlates with copy
number and are consistently overexpressed when amplified are likely to be
amplicon drivers and may be exploited as potential therapeutic targets.
Method
To identify potential novel therapeutic targets for subgroups of HER2
positive cancers, we have integrated high resolution genome wide microarray-based
comparative genomic hybridisation (aCGH) and matched gene expression data
obtained from 45 HER2 amplified primary breast carcinomas. We have used
Ingenuity Pathway Analysis (IPA) to identify pathways in which these targets
are enriched.
Results
Recurrent amplifications mapping to 95 loci were observed. 3967 genes whose
expression significantly correlates with copy number were identified, including
492 genes that were amplified in two or more cases. 369 genes were found to be
consistently overexpressed when amplified and mapped to recurrent amplicons in HER2
amplified cell lines. These included the potential therapeutic targets RAF1
(3p25), TOP2A (17q21), PPM1D (17q23), and AURKA (20q13).
IPA revealed that PI3K/AKT and neuregulin signalling, and DNA recombination and
repair pathways were significantly enriched for genes overexpressed when
amplified.
Our results have led to the identification of potential therapeutic targets for HER2 positive breast cancer and pathways that may drive the biology of these cancers. We are currently performing focused siRNA screens in 9 HER2 amplified and 6 control breast cancer cell lines, to identify genes whose silencing is selectively lethal in cells harbouring their amplification.
