Kinome profiling reveals breast cancer heterogeneity and identifies targeted therapeutic opportunities for triple negative breast cancer.
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.
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston QLD 4006, Australia.
Fares
F
Al-Ejeh
Mariska
M
Miranda
Wei
W
Shi
Peter T
PT
Simpson
Sarah
S
Song
Ana Cristina
AC
Vargas
Jodi M
JM
Saunus
Chanel E
CE
Smart
Mythily
M
Mariasegaram
Adrian P
AP
Wiegmans
Georgia
G
Chenevix-Trench
Sunil R
SR
Lakhani
Kum Kum
KK
Khanna
D000818:Animals; D016000:Cluster Analysis; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D040081:Protein Array Analysis; D011494:Protein Kinases / Q000032:analysis* / Q000096:biosynthesis*; D040901:Proteomics; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
D011494:Protein Kinases