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Page 238 Van Der Steen et al. Cancer Drug Resist 2018;1:230-49 I http://dx.doi.org/10.20517/cdr.2018.13

[91]
an EGFR exon 19 deletion . In these cells, the activation of IGF-1R or stimulation with TGF-β resulted in
a similar phenotype. Moreover, in reaction to EGFR-inhibition, it has been shown that increased EGFR-
IGF1R heterodimerization results in activation of mTOR, which in turn leads to de novo synthesis of EGFR
and survivin [92,93] . Downstream signaling of IGF-1R results in increased resistance against EGFR-inhibitors.
[95]
[94]
This mechanism of intrinsic resistance is observed with EGFR-TKI of the first [91-93] , second and third
generation. On the other hand, double inhibition of EGFR and IGF-1R at the same time can overcome this
resistance [96,97] .

FGFR
The fibroblast growth factor (FGF) family plays a role both in intrinsic and acquired resistance against
EGFR-TKIs. In NSCLC, the ligands FGF2, FGF9 and the receptors FGFR1 and FGFR2 have been reported
to be overexpressed [98,99] . Expression and activation of FGFR lead to a more mesenchymal phenotype and
downstream signaling activates MEK-ERK and PI3K signaling [100] . Upon response to an EGFR inhibitor
(erlotinib or gefitinib), FGF ligands and reporters become transcriptionally active [101] . Through the
[102]
activation of an autocrine loop, this activation leads to EGFR-TKI resistance . This resistance mechanism
[103]
has also been reported for afatinib , but to date not for acquired resistance to osimertinib or rociletinib.
PIK3CA
The PIK3CA gene encodes the 110kDa catalytic subunit of PI3K [104] , which is a downstream signaling
pathway of EGFR. The PIK3CA pathway generally confers intrinsic resistance to first- and second-line
EGFR inhibitors. In case of PIK3CA, both mutations and copy number gains are known aberrations.
Mutations that increase the catalytic activity of PIK3CA occur in 1%-10% of EGFR-mutant NSCLC
tumors [105,106] . Copy number gain (defined as > 2 copies per cell in over 40% of cells) is reported in
approximately 40% of NSCLC patients [107] . Both mutations and copy number gain are correlated with
a worse prognosis, overall survival and time to progression [105,107] . In case of EGFR-mutant tumors, 5/6
patients showed progressive disease when treated with EGFR-TKIs, 1 patient had treatment failure after
only 4 months of treatment with EGFR-TKIs [105] . A meta-analysis summarized the effects of PIK3CA
[108]
aberrations on treatment with diverse TKIs, amongst which are erlotinib, gefitinib and afatinib . Reports
on the effect of PIK3CA aberrations on osimertinib/rociletinib are not available yet.

BRAF
Overall, BRAF mutations can be considered as an intrinsic resistance mechanism but do not occur
frequently in NSCLC. Indeed, BRAF mutations can be found in only 1.5%-3.5% of NSCLC patients and
consists of a V600E mutation in about 50% of cases [109] . Concomitant mutations in EGFR and BRAF
are even more rare, with reported percentages around or below 1% of EGFR mutant NSCLC patients,
dependent on the study [110,111] . Crosstalk between BRAF and EGFR has been reported in a non-EGFR
[112]
mutant context . Hereby, the activation of BRAF results in the upregulation of EGFR ligands in a c-Jun
dependent way. This results in the activation of EGFR-MAPK signaling . It seems a logical step to assume
[112]
that activation of BRAF can bypass EGFR inhibition. Indeed, case reports described patients harboring
a BRAF V600E mutation during treatment with osimertinib [74,113] . In a peculiar case, a combination
of osimertinib with the BRAF inhibitor encorafenib resulted in significant inhibition of cell growth.
Unfortunately, the patient died before this combination treatment could be administered [113] . Nevertheless,
this strategy can be extended to other cases of EGFR-TKI resistance through BRAF mutations.

PTEN
Phosphatase and tensin homologue (PTEN) is a tumor suppressor. Loss of PTEN is reported in about 5%
of EGFR mutant NSCLC patients [106] and is linked to intrinsic resistance against EGFR-TKIs [114] . PTEN
is a link between EGFR and Akt signaling. When PTEN is lost, EGFR signaling is uncoupled from Akt
signaling. Inhibition of EGFR no longer results in inhibition of Akt signaling, resulting in resistance to