Oncotarget

Research Papers:

Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer

Fares Al-Ejeh, Mariska Miranda, Wei Shi, Peter T. Simpson, Sarah Song, Ana Cristina Vargas, Jodi M. Saunus, Chanel E. Smart, Mythily Mariasegaram, Adrian P. Wiegmans, Georgia Chenevix-Trench, Sunil R. Lakhani and Kum Kum Khanna _

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Oncotarget. 2014; 5:3145-3158. https://doi.org/10.18632/oncotarget.1865

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Abstract

Fares Al-Ejeh1*, Mariska Miranda1,2, Wei Shi1, Peter T. Simpson3, Sarah Song4, Ana Cristina Vargas3, Jodi M. Saunus3, Chanel E. Smart3, Mythily Mariasegaram3, Adrian P. Wiegmans1, Georgia Chenevix-Trench5, Sunil R. Lakhani3,6,7, and Kum Kum Khanna1,2*

1 Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston QLD 4006, Australia

2 The University of Queensland, St Lucia QLD 4072, Australia

3 The University of Queensland, UQ Centre for Clinical Research, Herston QLD 4029, Australia

4 The University of Queensland, QLD Centre for Medical Genomics, St Lucia QLD 4072, Australia

5 Cancer Genetics Laboratory, QIMR Berghofer Medical Research Institute, Herston QLD 4006, Australia

6 The University of Queensland, School of Medicine, Herston QLD 4006, Australia

7 Pathology Queensland: The Royal Brisbane & Women’s Hospital, Herston QLD 4029, Australia

Correspondence:

Kum Kum Khanna, email:

Fares Al-Ejeh, email:

Keywords: Breast cancer, TNBC, kinome, cancer heterogeneity, targeted therapy

Received: February 11, 2014 Accepted: March 24, 2014 Published: March 26, 2014

Abstract

Our understanding of breast cancer heterogeneity at the protein level is limited despite proteins being the ultimate effectors of cellular functions. We investigated the heterogeneity of breast cancer (41 primary tumors and 15 breast cancer cell lines) at the protein and phosphoprotein levels to identify activated oncogenic pathways and developing targeted therapeutic strategies. Heterogeneity was observed not only across histological subtypes, but also within subtypes. Tumors of the Triple negative breast cancer (TNBC) subtype distributed across four different clusters where one cluster (cluster ii) showed high deregulation of many proteins and phosphoproteins. The majority of TNBC cell lines, particularly mesenchymal lines, resembled the cluster ii TNBC tumors. Indeed, TNBC cell lines were more sensitive than non-TNBC cell lines when treated with targeted inhibitors selected based on upregulated pathways in cluster ii. In line with the enrichment of the upregulated pathways with onco-clients of Hsp90, we found synergy in combining Hsp90 inhibitors with several kinase inhibitors, particularly Erk5 inhibitors. The combination of Erk5 and Hsp90 inhibitors was effective in vitro and in vivo against TNBC leading to upregulation of pro-apoptotic effectors. Our studies contribute to proteomic profiling and improve our understanding of TNBC heterogeneity to provide therapeutic opportunities for this disease.


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