can inhibit the signaling of MAPK and PI3K pathways in patients with
overexpressing EGFR and HER2. In particular, the response to lapatinib is linked
to HER2 overexpression. The dual specificity of this drug results in inhibition of
phosphorylation of AKT, RAF, and ERK. Interestingly, breast cancer patients
positive for HER2 amplification with brain metastases are treated with lapatinib in
combination with capecitabine for improvement of survival rates [24–27]. Gefitinib
is an inhibitor targeting selectively EGFR (Fig. 1). Patients with locally advanced or
metastatic NSCLC experienced beneficial outcome when treated with gefitinib
[28]. In addition, treatment of EGFR mutation-positive NSCLC patients with
gefitinib improved progression-free survival in comparison with chemotherapy.
This was the first study that showed longer progression-free survival of patients
treated with selective therapy compared to classic chemotherapy [29, 30]. Erlotinib
(another kinase inhibitor targeting EGFR) is used for treatment of locally advanced
or metastatic NSCLC (Fig. 1). A clinical study published in 2011 revealed that use of
erlotinib prolongs survival of NSCLC patients, previously treated with first-line
chemotherapy, leading to its approval for this use [31]. In addition, erlotinib
combined with gemcitabine increases overall survival of patients with unresectable
pancreatic cancer positive for mutant EGFR [32]. Despite providing therapeutic
benefit, use of erlotinib has severe side effects such as breathing abnormalities, skin
rush, diarrhea, and cough, and the recommended dosage is close to the maximum
tolerated dose [33].
Afatinib is an irreversible inhibitor of ErbB family of kinase receptors (Fig. 1). As
a first-line treatment of patients with lung adenocarcinoma carrying activating
mutations in EGFR, afatinib increased progression-free survival but not overall
survival, when compared to gefitinib [34]. In addition, the LUX-Lung 6 trial
revealed that patients with advanced lung adenocarcinoma treated with afatinib
had prolonged progression-free survival and time to treatment failure in comparison
with those treated with gemcitabine in combination with cisplatin [35].
3 ALK Inhibitors
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor. In 1994, ALK was
described for the first time as a component of a fusion protein derived from
translocation t2;5 in anaplastic large cell lymphoma [36]. Several years later, the
full length of ALK receptor tyrosine kinase was characterized. It consists of an
extracellular ligand-binding domain, a transmembrane domain, and an intracellular
kinase domain that shares high similarity with the insulin receptor
(ER) [37, 38]. Although the physiological function of ALK is not completely
revealed, it has been described to play a critical role in early embryo development
and neural system development [38–41]. Furthermore, activation of ALK is
involved in activation of PI3K-AKT, CRKL-C3G, MEKK2/3-MEK5-ERK5,
JAK-STAT, and MAPK signaling pathways [38, 42–45]. Around 3–7% of
NSCLC patients (usually non-smokers) have a particular mutation, where
132
A. Moschopoulou et al.
overexpressing EGFR and HER2. In particular, the response to lapatinib is linked
to HER2 overexpression. The dual specificity of this drug results in inhibition of
phosphorylation of AKT, RAF, and ERK. Interestingly, breast cancer patients
positive for HER2 amplification with brain metastases are treated with lapatinib in
combination with capecitabine for improvement of survival rates [24–27]. Gefitinib
is an inhibitor targeting selectively EGFR (Fig. 1). Patients with locally advanced or
metastatic NSCLC experienced beneficial outcome when treated with gefitinib
[28]. In addition, treatment of EGFR mutation-positive NSCLC patients with
gefitinib improved progression-free survival in comparison with chemotherapy.
This was the first study that showed longer progression-free survival of patients
treated with selective therapy compared to classic chemotherapy [29, 30]. Erlotinib
(another kinase inhibitor targeting EGFR) is used for treatment of locally advanced
or metastatic NSCLC (Fig. 1). A clinical study published in 2011 revealed that use of
erlotinib prolongs survival of NSCLC patients, previously treated with first-line
chemotherapy, leading to its approval for this use [31]. In addition, erlotinib
combined with gemcitabine increases overall survival of patients with unresectable
pancreatic cancer positive for mutant EGFR [32]. Despite providing therapeutic
benefit, use of erlotinib has severe side effects such as breathing abnormalities, skin
rush, diarrhea, and cough, and the recommended dosage is close to the maximum
tolerated dose [33].
Afatinib is an irreversible inhibitor of ErbB family of kinase receptors (Fig. 1). As
a first-line treatment of patients with lung adenocarcinoma carrying activating
mutations in EGFR, afatinib increased progression-free survival but not overall
survival, when compared to gefitinib [34]. In addition, the LUX-Lung 6 trial
revealed that patients with advanced lung adenocarcinoma treated with afatinib
had prolonged progression-free survival and time to treatment failure in comparison
with those treated with gemcitabine in combination with cisplatin [35].
3 ALK Inhibitors
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor. In 1994, ALK was
described for the first time as a component of a fusion protein derived from
translocation t2;5 in anaplastic large cell lymphoma [36]. Several years later, the
full length of ALK receptor tyrosine kinase was characterized. It consists of an
extracellular ligand-binding domain, a transmembrane domain, and an intracellular
kinase domain that shares high similarity with the insulin receptor
(ER) [37, 38]. Although the physiological function of ALK is not completely
revealed, it has been described to play a critical role in early embryo development
and neural system development [38–41]. Furthermore, activation of ALK is
involved in activation of PI3K-AKT, CRKL-C3G, MEKK2/3-MEK5-ERK5,
JAK-STAT, and MAPK signaling pathways [38, 42–45]. Around 3–7% of
NSCLC patients (usually non-smokers) have a particular mutation, where
132
A. Moschopoulou et al.