Receptor tyrosine kinase inhibitors in cancer

Abstract

Targeted therapy is a new cancer treatment approach, involving drugs that particularly target specific proteins in cancer cells, such as receptor tyrosine kinases (RTKs) which are involved in promoting growth and proliferation, Therefore inhibiting these proteins could impede cancer progression. An understanding of RTKs and the relevant signaling cascades, has enabled the development of many targeted drug therapies employing RTK inhibitors (RTKIs) some of which have entered clinical application. Here we discuss RTK structures, activation mechanisms and functions. Moreover, we cover the potential effects of combination drug therapy (including chemotherapy or immunotherapy agents with one RTKI or multiple RTKIs) especially for drug resistant cancers.

Keywords: Cancer therapy; Drug resistance; Immune therapy; RTK inhibitors; Targeted therapy.

Fig. 1

Classical model of RTK activation mechanism. Upon ligand binding, RTKst undergo dimerization and trans-autophosphorylation of the kinase insert. The juxtamembrane domain, activation loop and the C-terminal tail are dislocated away from the kinase activation site, so ATP binding and phosphorylation can take place. This causes secondary transphosphorylations (shown in “RTKIs and cancer therapy” section) in the RTK kinase domains, creating docking sites for the binding of different intracellular signal proteins involved in cell growth, proliferation, and metastasis-associated signaling cascades

Fig. 2

An overview of inhibition of cell cycle proliferation, differentiation, survival, angiogenesis, and also enhancement of cell death pathways by receptor tyrosine kinase inhibitors (RTKIs) that target tyrosine kinase receptors. Different kinase inhibitors in each box have been tested in different cancers and are listed according to the specificity and selectivity of the kinase receptor. A Monocolonal antibodies (mAbs) can target RTKs or ligands and inhibit RTK activation. B Small molecule inhibitors can target the ATP-binding site of RTKs in their interacellular domain and inhibit RTK phosphrylation. Therefore, the signaling cascade is blocked. FLT3 FMS-like tyrosine kinase-3; RET rearranged during transfection; FGFR fibroblast growth factor receptor; VEGFR vascular endothelial growth factor receptor; EGFR epidermal growth factor receptor; c-KIT Mast/Stem Cell Growth Factor Receptor Kit; PDGFR platelet-derived growth factor receptor; PI3K phosphoinositide 3-kinase; Akt V-Akt murine thymoma viral oncogene homolog; mTOR mammalian target of rapamycin; PLCG1/PKC phospholipase C gamma 1/protein kinase C; RAS rat sarcoma virus; RAF rapidly accelerated fibrosarcoma; STAT3 signal transducer and activator of transcription 3; MAPK/ERK mitogen-activated protein kinase/extracellular signal-regulated kinase