Receptor tyrosine kinases (RTKs) are well known to drive cancer progression and metastasis when mutated or aberrantly expressed (1). However, the suboptimal efficacy of small-molecule inhibitors that target the downstream signaling events initiated by oncogenic RTKs indicates that noncanonical mechanisms are also contributing to RTK-dependent malignant progression.
An exciting study by Hsu et al. identifies how an RTK operates through a noncanonical pathway to promote colorectal cancer (CRC) malignancy (2). The authors examined the role of TYRO3 (a TAM (TYRO3, AXL, and MER) family RTK) in CRC progression using a number of in vitro techniques, human CRC tissue samples, organoids, and mouse models. They found that matrix metalloproteinase-2 (MMP-2) proteolytically cleaves TYRO3, which leads to its nuclear translocation. Nuclear TYRO3 then phosphorylates bromodomain-containing protein 3 (BRD3), an acetyl-lysine reader and epigenetic regulator, that binds genes related to cell growth, epithelial-mesenchymal transition (EMT), and metastasis. The researchers show that inhibition of MMP-2 or BRD3 abrogates the protumor effects of nuclear TYRO3. Thus, the work by Hsu et al. not only describes the MMP-2/TYRO3/BRD3 axis that appears to be crucial for the malignancy of some CRCs, but also reinforces the idea that targeting noncanonical pathways may lead to better therapies for oncogenic RTK-related malignancies.
GeneTex offers a very extensive catalog of antibody reagents for cancer biology research, including the MMP2 antibody (GTX104577), Caspase 3 antibody (GTX110543), SLUG antibody (GTX128796), Lamin A + C antibody (GTX101127), and ZEB1 antibody (GTX105278) cited in the Hsu et al. paper.
