Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • millimolar to molar Receptor tyrosine kinases RTKs consist o

    2021-09-26

    Receptor tyrosine kinases (RTKs) consist of 20 subfamilies in humans, all of which share a common structure consisting of extracellular ligand-binding region, a single-pass transmembrane domain and an intracellular tyrosine kinase domain [2]. Binding of a growth factor to the ligand-binding domain results in RTK activation and initiation of intracellular signalling cascades, which lead to cellular effects. Fibroblast growth factor (FGF) signalling mediated by its high-affinity tyrosine kinase receptors, FGF receptors (FGFRs) is known to instigate a range of responses in different cell types, and is regulated by its complex expression patterns and binding specificity of the FGF ligands and receptors as well as their isoforms [3], [4]. FGF signalling is probably most well-known for its regulatory function in multiple developmental processes including mesodermal patterning in the millimolar to molar [5] and subsequent formation of numerous organ systems [6]. In adult, it contributes to tissue homeostasis, as well as tissue repair, angiogenesis and inflammation [3], [4], [7]. Given such a plethora of biological effects that FGF signalling lead to, it may not be surprising that its deregulation can have significant consequences in carcinogenesis.
    FGF signalling via high-affinity receptor FGFR
    FGFR in cancer A large amount of evidence now indicates that alteration of FGF function, deregulated at one point within the FGF signalling cascade, could lead to cancer, based on in vitro and in vivo studies using both model and clinical materials. Below, we discuss the originating mutational events at the gene level and the corresponding consequence in tumour formation and progressions reported so far (Table 2).
    FGFR as a target of therapy Several FGFR tyrosine kinase inhibitors (TKIS) are currently in phase I/II clinical trials [170], [171], [172], [173], [174], [175], [176]. All these inhibitors also inhibit VEGFR, due to the high structural similarity of the kinase domains. Although at first it may beneficial to inhibit both angiogenesis and proliferation, many of these multiple targeting TKIs may be relatively less potent as inhibitors against FGFRs. This also increases the side effect profile, limiting the deliverability of the drug at doses necessary for inhibition of FGF signalling. AstraZeneca compound AZD4547 in a dual FGFR1 and 2 inhibitor currently in phase 1 trials against advance solid malignancies [177]. Similarly Novartis have 2 compounds in their development pipeline. Dovitinib is an inhibitor of both VEGFR and FGFRs in phase III development against renal cell carcinoma and phase II development in advanced breast cancer, relapsed MM and bladder cancer. Their other compound BGJ398 is a selective inhibitor of FGFRs, with the phase I study currently on-going [178]. GP369, an FGFR2-IIb-specific antibody has been used in vitro and in vivo to suppress the IIIb isoform in FGFR2 amplified human breast and gastric cancer cell lines [86]. Thus, the field is currently developing TKIs highly specific to FGFR. As a proof-of-principle, pan-FGFR inhibitors have been demonstrated to be effective in PTEN null FGFR2 mutant cell lines [124]. Treatment with the compound PD173074 resulted in cell death and cell cycle arrest of endometrial cancer cell lines [124]. The effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. In a small cell lung cancer model, PD173074 acts to impair cell proliferation both in cell lines and in xenograft tumours [179]. An alternative approach to TKIs is the FGF ligand traps which act as FGF ‘sponges’, binding multiple FGFs, leading to both anti-proliferative and anti-angiogenic effects such as the Five Prime drug FP-1039 [180]. This has demonstrated efficacy in a variety of preclinical in vivo and in vitro models. Another approach involves the use of FGFR blocking antibodies. Since antibodies are supposed to be specific to particular FGFRs, they limit pan-FGFR inhibition toxicity. One of the examples is the R3Mab antibody, which targets FGFR3, demonstrating anti-proliferative effects on xenografts of bladder cancer and t(4;14) myeloma cells [59]. A final approach utilises FGF ligands to super stimulate FGFRs. A recombinant FGF7 ligand has been developed for use in mucostitis, induced by myelotoxic therapy [181].