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

Al-Ejeh, Fares, Miranda, Mariska, Shi,Wei, Simpson, Peter T., Song, Sarah, Vargas, Ana Cristina, Saunus, Jodi M., Smart, Chanel E., Mariasegaram, Mythily, Wiegmans, Adrian P., Chenevix-Trench, Georgia, Lakhani, Sunil R. and Khanna, Kum Kum (2014) Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer. Oncotarget, 5 10: 3145-3158.

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Author Al-Ejeh, Fares
Miranda, Mariska
Shi,Wei
Simpson, Peter T.
Song, Sarah
Vargas, Ana Cristina
Saunus, Jodi M.
Smart, Chanel E.
Mariasegaram, Mythily
Wiegmans, Adrian P.
Chenevix-Trench, Georgia
Lakhani, Sunil R.
Khanna, Kum Kum
Title Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer
Journal name Oncotarget   Check publisher's open access policy
ISSN 1949-2553
Publication date 2014
Year available 2014
Sub-type Article (original research)
Open Access Status File (Author Post-print)
Volume 5
Issue 10
Start page 3145
End page 3158
Total pages 14
Place of publication Albany, NY United States
Publisher Impact Journals LLC
Collection year 2015
Language eng
Subject 2730 Oncology
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.
Keyword Breast cancer
Cancer heterogeneity
Kinome
Targeted therapy
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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