Identification of novel therapeutic targets for triple negative breast cancer through integrative kinomics


Session type:

Roger Daly1
1Department of Biochemistry and Molecular Biology, Monash University


Triple negative breast cancers (TNBCs) present a major clinical problem due to their aggressive nature and lack of effective targeted therapies. Consequently, there is a major need to identify therapeutic targets for this disease subgroup. We have addressed this problem via two programs of research that integrate mass spectrometry (MS)-based proteomics with functional genomic screens. In the first, MS-based tyrosine phosphorylation profiling subclassified a large TNBC cell line panel into distinct subgroups, and protein kinases exhibiting subgroup-selective activation profiles were identified by MS. Subsequent functional screens revealed opportunities for drug repurposing (eg specific FGFRs) and novel therapeutic targets. The second approach exploited our previous finding that TNBC is characterized by a prominent Src family kinase-dependent signalling network. Definition of the global impact of oncogenic Src on the expressed kinome, and then functional annotation of Src-regulated kinases, revealed several kinases essential for Src-induced transformation, including SGK1. In TNBC cells, Src positively regulated SGK1 expression and combined inhibition of Src and SGK1 was more effective than either treatment alone in inhibiting colony formation in vitro and tumour growth in nude mice. Therefore, this approach not only provides major mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.