Abstract
In the last decade, LMTK3 (lemur tyrosine kinase 3) has emerged as an important player in breast cancer, contributing to the advancement of disease and the acquisition of resistance to therapy through a strikingly complex set of mechanisms. Although the knowledge of its physiological function is largely limited to receptor trafficking in neurons, there is mounting evidence that LMTK3 promotes oncogenesis in a wide variety of cancers. Recent studies have broadened our understanding of LMTK3 and demonstrated its importance in numerous signalling pathways, culminating in the identification of a potent and selective LMTK3 inhibitor. Here, we review the roles of LMTK3 in health and disease and discuss how this research may be used to develop novel therapeutics to advance cancer treatment.
Highlights
LMTK3 was shown to bind to DEAD-box RNA helicase p68 (DDX5) and the pri-miRNAs of these three miRNAs, promoting their processing into pre-miRNA but inhibiting further processing into functional miRNAs, thereby protecting itself from downregulation [30,31]. miR-34a is known to have a tumour suppressor role; this study further demonstrated that the oncogenic miRNA, miR-182, has a tumour suppressor role in breast cancer cells overexpressing LMTK3, highlighting the complex signalling network surrounding LMTK3 regulation
LMTK3 overexpression desensitized cells to aromatase inhibitors (AIs). These findings suggest that LMTK3 is upregulated upon treatment with AIs through MIR2052HG and EGR1 where it may contribute to AI resistance through ERα upregulation and stabilization [32]
The studies discussed above portray LMTK3 as an exceptionally versatile protein kinase and highlight its complex role both in normal physiology and pathological conditions, most notably cancer
Summary
LMTK3 (lemur tyrosine kinase 3) has gained attention in recent years due to the growing evidence of its involvement in a multitude of cancers [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35]. LMTK3, known as LMR3 or AATYK3, belongs to the LMTK (LMR or AATYK) family of kinases, along with LMTK1 ( known as LMR1 or AATK) and LMTK2 ( known as LMR2, BREK, KPI2 or AATYK2) This family of kinases performs a wide range of functions in cell signalling and membrane trafficking, while aberrancies in these proteins are linked to diseases such as cystic fibrosis, Alzheimer’s disease and cancer [36,37,38,39,40]. This research led to the discovery of a potent and selective LMTK3 inhibitor, namely, ‘C28’ This compound slowed cancer growth in xenograft models, demonstrating the therapeutic potential of pharmacological LMTK3 inhibition. Through further structural and functional studies, this significant finding will accelerate the translation of this research into the clinic with great promise to improve cancer therapy
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