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Page 328 White et al. Cancer Drug Resist 2019;2:326-34 I http://dx.doi.org/10.20517/cdr.2019.16
[22]
aspect of cancer initiation and progression . Overexpression of TKs, as a result of gene amplification,
in human cancers leads to an increase in the local concentration of the receptor TKs and consequent
[23]
elevation of TK signaling . Chromosomal rearrangements lead to the formation of new TK fusion
[24]
oncoproteins, such as the BCR-ABL fusion protein . Identification of such chromosomal rearrangements
and the associated fusion oncoprotein can be instrumental to the development of new therapeutics as these
fusion proteins are often good targets for small molecule inhibitors. Finally, autocrine activation refers to a
situation where the cells are constantly secreting extra-cellular ligands that bind to receptors on the same
cells, leading to the activation of specific TK pathways . Autocrine activation of TKs has been identified
[25]
[26]
and studied in various types of cancers, including HGF-MET in AML and SCF-KIT autocrine loop in
small cell lung cancer .
[27]
The effect of constitutively active TKs can be blocked through the use of TKIs, which have been found to
[1]
be effective in the targeted treatment of various malignancies . Imatinib was the first TKI to be developed
for use against chronic myelogenous leukemia (CML) and was the first TKI successfully introduced
[14]
[28]
in clinical oncology . Imatinib targets the BCR-ABL TK that is selectively expressed by CML cells and
promotes their uncontrolled proliferation.
Since then, numerous TKIs have been discovered and developed as anti-cancer treatments targeting a vast
array of cancer types. These inhibitors include gefitinib [29,30] and erlotinib; two oral anti-cancer treatments
that act as selective inhibitors of the TK domain of the EGFR. These drugs are approved for the treatment
of lung cancer [22,23] and non-small cell lung cancer and pancreatic cancer [31-33] respectively. Ibrutinib is a
first-in-class small molecule inhibitor of Bruton’s tyrosine kinase (BTK) and is used to treat B cell cancers
[35]
[34]
such as mantle cell lymphoma and Waldenström’s macroglobulinemia .
Subsequently, the activity of TKIs has been widened by designing molecules that target more than one
enzyme. For example Sunitinib, an oral, small-molecule, multi-targeted receptor (PDGFR and VEGFR
families) TKI was the first cancer drug to be approved for two indications, renal cell carcinoma (RCC) and
imatinib-resistant gastrointestinal stromal tumour , at the same time. Most recently, dasatinib, another
[36]
[37]
[38]
multi-targeted TKI developed to contrast imatinib resistance and enhance TKI tolerability in patients
with CP-CML, was approved for the treatment of CML and ALL [39,40] .
Cabozantinib is a newly developed small molecule inhibitor of the tyrosine kinases c-MET and VEGFR2
[42]
[41]
that is used to treat medullary thyroid cancer and a first-line treatment for advanced RCC , amongst
other cancer types. Vandetanib is a small molecule TKI that targets key signaling pathways in cancer by
inhibiting VEGFR-dependent tumour angiogenesis and EGFR- and RET-dependent cell proliferation and
survival, and is used to treat tumours of the thyroid gland [43,44] . Trametinib is another first-in-class TKI,
that acts as an allosteric inhibitor of MEK1 and MEK2 and which is approved for treatment of metastatic
melanoma harboring the BRAF V600 mutation .
[45]
Interestingly, the TKI ruxolitinib was the first small molecule inhibitor of JAK1/2 kinases which was used
[46]
in the treatment of myelofibrosis, applied to the field of myeloproliferative neoplasms and as a result of
the promising results achieved in clinical trials, approved for the treatment of myelofibrosis by the U.S.
FDA [47,48] . The most recent receptor tyrosine kinase to be approved is lorlatinib, the first third-generation
anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK-positive
[49]
metastatic non-small cell lung cancer .
It is important to note that while the small molecules mentioned above, are mainly used to target TKs,
other types of inhibitors such as monoclonal antibodies (mAbs) can also be used to target TKs. At present,
[50]
more than 70 mAbs have been approved by the EMEA and FDA for therapeutic use and the number of