Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Abstract

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

“…Overexpression of various types of RTKs is found in different types of cancer, which encouraged medicinal chemists worldwide to develop numerous RTKs inhibitors [ 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ]. Among these efforts, several DDR kinase inhibitors have been discovered so far, some of them have been demonstrated to possess a promising therapeutic potential.…”

Combinatorial Strategies to Target Molecular and Signaling Pathways to Disarm Cancer Stem Cells

“…The combinatorial strategies herein reported foresee the targeting of developmental and oncogenic signaling pathways that are key players in defining several features of CSCs biology, including self-renewal, stemness, EMT, CSCs dormancy, as well as drug resistance, radio-resistance, tumor initiation and dedifferentiation, widely discussed in many published reviews (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

“…Developmental signaling pathways [including Wnt, Sonic Hedgehog (Shh) and Notch] and oncogenic cascades (including transforming growth factor-beta (TGF-b), Janus kinase/signal transducer and activator of transcription 3 (JAK/ STAT3), phosphatidylinositol 3-kinase/V-Akt murine thymoma viral oncogene/mammalian target of rapamycin (PI3K/AKT/ mTOR), Mitogen-activated protein kinase (MAPK) and V-SRC avian sarcoma (Src) have been identified as key players both in CSCs biology maintenance and in cancer therapy resistance (17,18). The description of these signaling pathways and their roles in defining the biology of CSCs will not be tackled herein and the reader is invited to refer to reviews that widely discuss these topics (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Although several targeted approaches relying on monotherapy have been developed to affect these pathways, they have shown limited efficacy due to the activation of bypass pathway(s) and to the complexity of signaling networks containing feedback loops and cross-talk.…”

Protein Kinases in Leukemias

“…Indeed, combination therapy has several advantages. First, targeting two independent molecular pathways leaves less opportunity for escape mechanisms, illustrated by the crosstalk between kinases and phosphatases in CML [ 11 , 12 ]. Second, if the molecules used in combination show synergy, they can then be used with efficacy at lower doses, which means lower secondary effects for patients.…”

“…Second, if the molecules used in combination show synergy, they can then be used with efficacy at lower doses, which means lower secondary effects for patients. Finally, considering the heterogeneity of leukemia samples, combination therapy is more likely to benefit to large number of patients than single therapy with PK inhibitors [ 1 , 8 , 12 ].…”