Second-generation VEGFR/multikinase inhibitors include pazopanib,
cabozantinib, lenvatinib, axitinib, and vandetanib (Fig. 3). All of them have been
approved by the FDA for the treatment of one or several cancer types including
thyroid cancer, RCC, soft tissue sarcoma, and medullary thyroid cancer [78].
5 BCR-ABL Inhibitors
The ABL protein family consists of two members: c-ABL and ARG.
Physiologically, c-ABL is involved in actin remodeling, cell adhesion, motility,
DNA damage response, and microbial pathogen response. In several types of cancer,
deregulation and uncontrolled expression of c-ABL kinase has been described
[79, 80]. When phosphorylated, c-ABL induces activity of downstream targets,
activating ERK5, RAC/JNK, and STAT 1/3 pathways. C-ABL is also a molecular
component driving CML. Translocation of part of chromosome 9 to chromosome
22 (Philadelphia chromosome) leads to the expression of oncogenic fusion protein
BCR-ABL [81] highlighting ABL is an important target for the development of
selective inhibitors. Imatinib was the first kinase inhibitor to be approved by FDA
(2001) (Fig. 4). It is an inhibitor of three different targets: ABL, mast/stem cell
growth factor receptor (tyrosine kinase KIT or CD117), and PDGFR [82]. After
phase-III clinical trial showed improved cytogenetic response rates of CML patients
treated with imatinib, the drug was accepted for treatment of CML in blast, accelerated, and chronic phases [83]. Later, in 2002 and 2008, imatinib was approved also
for treatment of GIST both for advanced, metastatic tumors and previously resected
tumors [84, 85]. Unfortunately, imatinib treatment is not successful in around 30%
of patients [86]. The reason is acquired resistance, based on either a reduced cellular
uptake of the drug, an increased activity of efflux transporters, or point mutations
leading to conformational changes of BCR-ABL and therefore to a reduced binding
to imatinib. In addition, resistance is acquired by amplification and overexpression
of BCR-ABL gene [87]. Second-generation ABL inhibitors such as nilotinib,
dasatinib, and bosutinib were developed, in order to overcome mutation-related
resistance (Fig. 4). They were all approved for the treatment of CML: nilotinib
and dasatinib as first- or second-line treatment and bosutinib as second-line therapy
[88]. Nilotinib showed highly promising results because it was potent against almost
all mutations resulting in BCR-ABL-dependent resistance [89]. Dasatinib showed
high potency in patients with chronic phase CML and a faster treatment response
when it was compared to imatinib [90]. Due to its unique structure, dasatinib is also
potent against some conformation-altering mutations of BCR-ABL
[91, 92]. Bosutinib has a much different structure. It was initially designed as a
SRC inhibitor but found to have activity against ABL [93]. Although bosutinib is not
potent against major resistant mutants and does not have high selectivity for
BCR-ABL, it has the benefit to be not sensitive to resistance efflux transporters
and remains in the cells [94, 95]. Therefore, bosutinib is approved for second-line
treatment of CML, while trials that test it as first-line treatment are ongoing [88, 96]
(Fig. 4).
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cabozantinib, lenvatinib, axitinib, and vandetanib (Fig. 3). All of them have been
approved by the FDA for the treatment of one or several cancer types including
thyroid cancer, RCC, soft tissue sarcoma, and medullary thyroid cancer [78].
5 BCR-ABL Inhibitors
The ABL protein family consists of two members: c-ABL and ARG.
Physiologically, c-ABL is involved in actin remodeling, cell adhesion, motility,
DNA damage response, and microbial pathogen response. In several types of cancer,
deregulation and uncontrolled expression of c-ABL kinase has been described
[79, 80]. When phosphorylated, c-ABL induces activity of downstream targets,
activating ERK5, RAC/JNK, and STAT 1/3 pathways. C-ABL is also a molecular
component driving CML. Translocation of part of chromosome 9 to chromosome
22 (Philadelphia chromosome) leads to the expression of oncogenic fusion protein
BCR-ABL [81] highlighting ABL is an important target for the development of
selective inhibitors. Imatinib was the first kinase inhibitor to be approved by FDA
(2001) (Fig. 4). It is an inhibitor of three different targets: ABL, mast/stem cell
growth factor receptor (tyrosine kinase KIT or CD117), and PDGFR [82]. After
phase-III clinical trial showed improved cytogenetic response rates of CML patients
treated with imatinib, the drug was accepted for treatment of CML in blast, accelerated, and chronic phases [83]. Later, in 2002 and 2008, imatinib was approved also
for treatment of GIST both for advanced, metastatic tumors and previously resected
tumors [84, 85]. Unfortunately, imatinib treatment is not successful in around 30%
of patients [86]. The reason is acquired resistance, based on either a reduced cellular
uptake of the drug, an increased activity of efflux transporters, or point mutations
leading to conformational changes of BCR-ABL and therefore to a reduced binding
to imatinib. In addition, resistance is acquired by amplification and overexpression
of BCR-ABL gene [87]. Second-generation ABL inhibitors such as nilotinib,
dasatinib, and bosutinib were developed, in order to overcome mutation-related
resistance (Fig. 4). They were all approved for the treatment of CML: nilotinib
and dasatinib as first- or second-line treatment and bosutinib as second-line therapy
[88]. Nilotinib showed highly promising results because it was potent against almost
all mutations resulting in BCR-ABL-dependent resistance [89]. Dasatinib showed
high potency in patients with chronic phase CML and a faster treatment response
when it was compared to imatinib [90]. Due to its unique structure, dasatinib is also
potent against some conformation-altering mutations of BCR-ABL
[91, 92]. Bosutinib has a much different structure. It was initially designed as a
SRC inhibitor but found to have activity against ABL [93]. Although bosutinib is not
potent against major resistant mutants and does not have high selectivity for
BCR-ABL, it has the benefit to be not sensitive to resistance efflux transporters
and remains in the cells [94, 95]. Therefore, bosutinib is approved for second-line
treatment of CML, while trials that test it as first-line treatment are ongoing [88, 96]
(Fig. 4).
136
A. Moschopoulou et al.