Targeted Therapies
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke in Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
The role of Src family kinases in cell signalling and morphologic transformation processes is well established. Nine members of the Src kinase family have been identified and they all belong to a family of non-receptor kinases that are involved in a number of signalling pathways controlling multiple functions such as cell adhesion, cell mobility, cell proliferation and terminal differentiation. They directly regulate several important signalling pathways including Ras/MAPK, PI3K/Akt and STAT3 (Martin 2001) and also play an important role in VEGF induced angiogenesis. The Src kinases are tyrosine kinases and participate in signal transduction in response to several stimuli, including angiogenic factors. The first defined proto-oncogene, c-Src is often overexpressed in many human malignant tumours, including HNC. Expression of activated c-Src is higher in tissues of human HNC than in normal mucosa and correlates with an invasive, poorly differentiated phenotype with more advanced nodal stage (Mandal et al. 2008).
Leukaemias
Pat Price, Karol Sikora in Treatment of Cancer, 2014
Following the success in the treatment of patients with CML in CP resistant/refractory or intolerant to imatinib, both dasatinib and nilotinib entered clinical trials for first-line therapy of the newly diagnosed patient in 2006.113,114 Dasatinib is a thiazole-carboxamide structurally unrelated to imatinib which binds to the ABL kinase domain (ABL KD) regardless of the conformation of the activation loop – whether open or closed. It also inhibits some of the Src family kinases. Preclinical studies showed that dasatinib was 300-fold more potent than imatinib and is active against 18 of 19 tested imatinib-resistant KD mutant subclones, with the notable exception of the T315I mutant. Nilotinib, like imatinib, acts by binding to the closed (inactive) conformation of the Abl-KD, but with a much higher affinity. Like imatinib, it inhibits the dysregulated tyrosine kinase activity of the Abl kinase by occupying the ATP-binding pocket of the oncoprotein and blocking the capacity of the enzyme to phosphorylate downstream effector molecules. In vitro studies suggest that nilotinib is approximately 30–50-fold more potent than imatinib mesylate. Nilotinib is also active in 32 of the currently 33 imatinib-resistant cell lines with mutant Abl kinases, but like imatinib and dasatinib has no activity against the Bcr-Abl1T315I mutation.
Fc Receptors
Maurizio Zanetti, J. Donald Capra in The Antibodies, 1999
A first set of tyrosine kinases that are activated via FcR are src family kinases. FcɛRI aggregation was shown to activate lyn in rat basophilic leukemia (RBL) cells and yes in the mouse mastocytoma cells PT18 [219, 220]. FcγRIIIA activate lck in NK cells [221]. FcγRI activate lck, lyn and hck in U937 treated with IFNγ [222]. Lyn is associated to FcRβ in resting mast cells [220, 223] and lyn-SH2 fusion proteins could precipitate tyrosine phosphorylated FcRβ in activated RBL cells [224]. Lck associates to and phosphorylates the TCRζ subunit of FcγRIIIA in human NK cells [225, 226].
De novo variant in tyrosine kinase SRC causes thrombocytopenia: case report of a second family
Published in Platelets, 2019
Lore De Kock, Chantal Thys, Kate Downes, Daniel Duarte, Karyn Megy, Chris Van Geet, Kathleen Freson
Proto-oncogene tyrosine-protein kinase SRC is a non-receptor tyrosine kinase protein that phosphorylates specific tyrosine residues in other proteins [1]. SRC is a member of the SRC family kinases (SFKs) and has been implicated in cancer. In advanced human colon cancer, a truncating somatic variant in SRC at codon 531 was reported in 12% of cases to cause activation of SRC and promote metastasis [2]. Currently, 38 tyrosine kinase inhibitors (TKIs) have already been developed for cancer treatment [3]. These TKIs mostly have a relatively high affinity for their corresponding targeted kinase, although they are never fully specific and often react with different SFKs. As the activation of platelets strongly relies on SFK activity, platelet-related side effects of TKIs have been described and comprise thrombocytopenia and the inhibition of platelet function. This can result in an increased bleeding risk, which is the case in almost 40% of TKIs currently used for cancer treatment [3].
Identification of imidazo[4,5-c]pyridin-2-one derivatives as novel Src family kinase inhibitors against glioblastoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Lishun Zhang, Zichao Yang, Huiting Sang, Ying Jiang, Mingfeng Zhou, Chuan Huang, Chunhui Huang, Xiaoyun Wu, Tingting Zhang, Xingmei Zhang, Shanhe Wan, Jiajie Zhang
Src family kinases (SFKs) are a group of non-receptor tyrosine kinases composed of 11 members, including eight main members, such as c-Src (Src), Fyn, Yes, Fgr, Lyn, Blk, Hck, and Lck7,8. They share a set of conserved domains which includes an N-terminal Src homology domain (SH4), followed by a unique domain, two Src homology domains (SH3 and SH2), a catalytic kinase domain (SH1), and a C-terminal regulatory tail9. SFKs are highly expressed in GBM cell lines and tumour samples, in which abnormal activation of SFKs induced multiple tumour-promoting effects, including reducing cell apoptosis, increasing angiogenesis, promoting cell proliferation, motility as well as invasion10–12. In detail, Yes and phosphatidylinositol 3-kinase bind prototypical death receptor CD95 to mediate invasion of GBM13. Hck stimulates GBM progression via mediating epithelial-mesenchymal transition process14. Lyn enhances GBM cell survival by promoting autophagy under nutrient deprivation15. More importantly, both Src and Fyn are downstream targets of EGFR oncogenic signalling, and their overexpression is frequently occurred in GBM patients. Glioblastoma exhibiting activated EGFR signalling also showed the activation of Src and Fyn, which indicates that Src and Fyn inhibition may improve the efficacy of anti-EGFR targeted therapy16–18.
The role of N-myristoyltransferase 1 in tumour development
Published in Annals of Medicine, 2023
Hong Wang, Xin Xu, Jiayi Wang, Yongxia Qiao
The myristoyl coenzyme A analogue B13 and its derivative LCL204 were identified as small molecule inhibitors of NMT [50]. B13 prevents Src myristoylation and Src localization to the cytoplasmic membrane and attenuates Src-mediated oncogenic signalling. B13 has anti-invasive and anti-tumour effects on prostate [50] and bladder cancer cells with low toxic effects [55]. The use of these small molecule inhibitors provides a promising approach to inhibiting Src family kinase-mediated oncogenic activity [50]. The organopalladium compound dibenzylideneacetone dipalladium (Tris-DBA), is another inhibitor of human NMT synthesis, that blocks the kinase activity of NMT1 and decreases its expression. Tris-DBA shows potent anti-proliferative activity against melanoma cells by inhibiting several proliferation-related signalling pathway proteins including MAPK, Akt and STAT-3 [69]. However, the poor solubility of Tris-DBA impairs its effectiveness. Excitingly, a study synthesized Tris-DBA-Pd hyaluronic acid nanoparticles and demonstrated that this nanoparticle is an effective treatment against CD44-positive tumours such as melanoma [70]. Drug-like inhibitors IMP-366 (DDD85646) and IMP-1088 deliver complete and specific inhibition of N-myristoylation. In cancer cell lines, IMP-366 downregulates cell cycle regulatory proteins, and upregulates proteins involved in ER stress and the unfolded protein response [58]. IMP-1088, another inhibitor of both NMTs, completely inhibits N-myristoylation in a range of cell lines at low nanomolar concentrations (100 nM) [71].
Related Knowledge Centers
- Lck
- NON-Receptor Tyrosine Kinase
- Proto-Oncogene Tyrosine-Protein Kinase Src
- Fyn
- Fgr
- Hck
- Tyrosine-Protein Kinase Blk
- Lyn
- Fyn-Related Kinase
- N-Terminus