Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors.
Cancer Res
; 77(1): 175-186, 2017 01 01.
Article
in En
| MEDLINE
| ID: mdl-27758886
ABSTRACT
Approximately 80% of breast cancers overexpress the kinase breast tumor kinase (BRK)/protein tyrosine kinase 6, which has various oncogenic roles in breast cancer cell proliferation, survival, and migration. However, BRK inhibitors have yet to be explored as possible therapeutic tools. In this study, we used a parallel compound-centric approach to discover a new class of pharmaceutical agents, exemplified by XMU-MP-2, as potent and selective BRK inhibitors. XMU-MP-2 exhibited target-specific inhibition of BRK kinase activity and disrupted signaling pathways mediated by this activity, thereby reducing proliferation in BRK-positive breast cancer cells. In mouse xenograft models, XMU-MP-2 repressed the growth of tumors driven by oncogenic BRK, including BRK-transformed Ba/F3 cells and BRK-positive breast cancer cells. Notably, XMU-MP-2 cooperated strongly with HER2 inhibitor or ER blockade to block breast cancer cell proliferation in vitro and in vivo Overall, our findings offer a preclinical proof of concept for therapeutic targeting of the BRK kinase in breast cancer. Cancer Res; 77(1); 175-86. ©2016 AACR.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein-Tyrosine Kinases
/
Breast Neoplasms
/
Protein Kinase Inhibitors
/
Neoplasm Proteins
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Cancer Res
Year:
2017
Document type:
Article
Affiliation country:
China