Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors

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.

BRK Phosphorylates SMAD4 for proteasomal degradation and inhibits tumor suppressor FRK to control SNAIL, SLUG and metastatic potential

“…We have also reported that BRK activation significantly enhances tumor formation in xenograft models (5). Additionally, BRK is overexpressed in over 80% of breast carcinomas (1), and in many other major cancer types including lung (11), ovarian (12), and pancreatic (13) cancers. Although the cellular role of BRK in carcinogenesis has been established, its role in controlling signal transduction pathways is still unclear.…”

“…Breast tumor kinase (BRK) is a non-receptor tyrosine kinase highly expressed in most breast cancer cell lines and tumors (1). It displays a similar architecture and 30-40% sequence identity with Src Family Kinases (SFKs) (2).…”

Phosphoproteomics Analysis Identifies Novel Candidate Substrates of the Nonreceptor Tyrosine Kinase, Src-related Kinase Lacking C-terminal Regulatory Tyrosine and N-terminal Myristoylation Sites (SRMS)

“…The phosphorylation of the activation loop tyrosine is a primary indicator of enzymatic activation in tyrosine kinases (15). Unlike c-Src (75) and BRK (76), no commercial antibodies exist to detect the phosphorylation of the SRMS activation-loop tyrosine residue (Y380). Additionally, whereas various specific chemical inhibitors of Src (77) and BRK (76) have been characterized, to our knowledge, no such specific inhibitors of SRMS enzymatic activity have been reported.…”

“…Unlike c-Src (75) and BRK (76), no commercial antibodies exist to detect the phosphorylation of the SRMS activation-loop tyrosine residue (Y380). Additionally, whereas various specific chemical inhibitors of Src (77) and BRK (76) have been characterized, to our knowledge, no such specific inhibitors of SRMS enzymatic activity have been reported. Considering these technical shortcomings, we reasoned that the overexpression of the catalytically active wild type SRMS kinase in human cells may represent a reasonably viable alternative strategy to identify the cellular substrates of the kinase.…”

Insight on mutation‐induced resistance to anaplastic lymphoma kinase inhibitor ceritinib from molecular dynamics simulations

“…Deregulation of kinase function is implicated in many types of cancer. This has aroused considerable interests in the molecular‐targeted drug discovery against diseases induced by kinase disorder . As a member of the receptor tyrosine kinase (RTK) superfamily, anaplastic lymphoma kinase (ALK) is normally expressed in the central and peripheral nervous system and participates in physiological development of embryos .…”