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Van Der Steen et al. Cancer Drug Resist 2018;1:230-49 I http://dx.doi.org/10.20517/cdr.2018.13 Page 237

(HGF)-cMET pathway. The amplification of cMET plays a role in the activation of cMET-downstream
signaling and thus circumvents EGFR-TKI inhibition. Amplification of cMET can be observed in
approximately 3% of TKI-naïve NSCLC cases, compared to 10%-20% of EGFR-TKI treated patients [69,70] .
The difference in percentage may represent acquired resistance. Secondly, when comparing downstream
[71]
signaling of EGFR and cMET, these pathways overlap . In vitro studies suggest a role in the reactivation
[17]
of Her3/ERBB3-PI3K-Akt signaling . This resistance mechanism is relevant for both the first- and third-
generation EGFR-TKIs [72-74] .

KRAS
KRAS mutation represents another important intrinsic resistance mechanism to EGFR inhibition in
[75]
NSCLC. KRAS mutations mainly occur in codon 12 (G12C/D/S/V) and codon 13 (G13C) . KRAS is a
downstream target of EGFR and normally becomes activated upon stimulation of EGFR. The mutations
render KRAS constitutively active, thereby making KRAS independent of EGFR-stimulation. Therefore
a patient harboring both sensitizing EGFR mutations concomitantly with KRAS-mutations is unlikely
[76]
to respond to EGFR-TKIs , since EGFR-downstream signaling will continue its signaling due to active
KRAS . This has been reported for both the first and third generation of EGFR-TKIs [77,78] .
[77]
Axl
Upregulation of the receptor tyrosine kinase Axl (anexelekto) is another intrinsic resistance mechanism
against erlotinib and gefitinib. For the second- and third- generation EGFR-TKIs no reports on Axl as
resistance mechanism are available. The resistance might be caused by either the upregulation of the
[79]
Axl receptor, or the upregulation of its ligand GAS6 . Two effects can be observed that might explain
the increased resistance against EGFR-TKIs. Firstly, Axl drives epithelial to mesenchymal transition
(EMT). Hence, Axl downregulation leads to a decrease of the EMT markers N-cadherin and vimentin
[80]
and the upregulation of E-cadherin . Secondly, since PI3K-Akt and MAPK/ERK signaling cascades are
[81]
downstream from both Axl and EGFR, increased activation of Axl can bypass EGFR-inhibition .
Her2
The Her2 receptor contains a kinase domain, but a ligand is still unknown. Her2 frequently dimerizes with
EGFR and thus stimulates downstream signaling. Intrinsic aberrations in Her2 include overexpression,
an insertion in exon 20 (G776 YVMA ) and amplification. It has been shown that, in case of Her2
[82]
overexpression and Her2 amplification [83,84] , EGFR-TKIs are still active in NSCLC patients. Despite of
[85]
reports in cell line models and mouse models , EGFR-TKIs can be active against non-mutated Her2.
Mutations in Her2 have been reported both in the kinase domain and in the transmembrane domain ,
[87]
[86]
however, their concomitance with EGFR mutations is not clear thus far. All generations of EGFR-TKIs can
inhibit non-mutant Her2 [82,88,89] . Due to the heterodimerization of EGFR with Her2, stimulation of EGFR
is often necessary to activate downstream signaling in case of non-mutant Her2. If EGFR is inhibited,
downstream signaling is inhibited. In case of mutations in Her2, the receptor often gains in kinase activity
and is no longer dependent on EGFR activation to initiate downstream signaling. However, these tumors
[86]
show responses to Her2-inhibitors like, e.g., trastuzumab or lapatinib .

For colorectal cancer (CRC), the situation is different. In case of EGFR mutations in CRC the monoclonal
anti-EGFR antibody cetuximab was the most effective treatment for patients. Since this antibody interferes
with ligand binding to EGFR, the mechanism of action is different from the EGFR-TKIs administered
in NSCLC, that block the kinase activity. Amplification of Her2 is a known resistance mechanism to
[90]
cetuximab that can be overcome by combining cetuximab with Her2 inhibitors .
IGF-1R
The insulin growth factor receptor 1 (IGF-1R) has been shown to induce EMT in NSCLC cells carrying