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

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.