Putting the BRK on breast cancer: From molecular target to therapeutics

Abstract

BReast tumor Kinase (BRK, also known as PTK6) is a non-receptor tyrosine kinase that is highly expressed in breast carcinomas while having low expression in the normal mammary gland, which hints at the oncogenic nature of this kinase in breast cancer. In the past twenty-six years since the discovery of BRK, an increasing number of studies have strived to understand the cellular roles of BRK in breast cancer. Since then, BRK has been found both in vitro and in vivo to activate a multitude of oncoproteins to promote cell proliferation, metastasis, and cancer development. The compelling evidence concerning the oncogenic roles of BRK has also led, since then, to the rapid and exponential development of inhibitors against BRK. This review highlights recent advances in BRK biology in contributing to the "hallmarks of cancer", as well as BRK's therapeutic significance. Importantly, this review consolidates all known inhibitors of BRK activity and highlights the connection between drug action and BRK-mediated effects. Despite the volume of inhibitors designed against BRK, none have progressed into clinical phase. Understanding the successes and challenges of these inhibitor developments are crucial for the future improvements of new inhibitors that can be clinically relevant.

Keywords: Breast tumor kinase (BRK); chemical inhibitors; hallmarks of cancer; meta-analysis; molecular inhibitors.

Figure 1

Structure and domains of BRK. The human BRK protein is a 451 amino acid kinase, which consists of 3 functional domains - SH3, SH2, and SH1 domain. The first two domains are required for interactions with other molecules, while the SH1 domain confers a catalytic role to the protein. Tyrosine 342 (Y342) is a phosphorylation site in the tyrosine kinase (TK) domain that increases BRK's activity, while tyrosine 447 (Y447) phosphorylation negatively regulates kinase activity , .

Figure 2

BRK signaling pathways. BRK is the converging point of a variety of signaling pathways that result in modulation of different hallmarks of cancer.

Figure 3

Clinical characterization of BRK expression level in cancer. Boxplot of PTK6 expression (y-axis) in normal (blue) and tumor (red) of the TCGA carcinoma cohorts. (BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical and endocervical cancers; CHOL, cholangiocarcinoma; COADREAD, colorectal carcinoma; ESCA, esophageal carcinoma; GBMLGG, glioblastoma and low grade glioma; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; SARC, sarcoma; STAD, stomach adenocarcinoma; THCA, thyroid carcinoma; THYM, thymoma; and UCEC, uterine corpus endometrial carcinoma).