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EGFR-TKIs [115] . This has been demonstrated in cell lines, where resistance to erlotinib or gefitinib was
correlated with PTEN levels. Overexpression of PTEN in cell lines with low/no PTEN levels resulted in
increased sensitivity to erlotinib or gefitinib [114,115] . Loss of PTEN is both known as a primary mechanism
[114]
[116]
of resistance (present in EGFR-TKI naïve patients) and as acquired mechanism of resistance . For the
latter, around 10% of patients without any other known resistance mechanisms are reported to have PTEN
[114]
loss .
TP53
In NSCLC, TP53 mutations occur in approximately 50% of patients. This is also the case in EGFR-mutated
NSCLC [117-119] . The influence of TP53 mutations on response and survival of TP53/EGFR double mutated
patients is not clear from literature. One report showed a significantly lower progression free survival in
case of TP53 exon 8 mutations and exon 19 deletions in EGFR [118] . However, two other studies reported no
significant effect in TP53/EGFR concomitant mutated patients [117,119] , so the role of TP53 mutations in EGFR-
TKI resistance is still unclear.

YAP
Yes-associated protein (YAP) is a part of the HIPPO-pathway, and seems to be associated with both
intrinsic and acquired resistance to EGFR-TKI. Several links between EGFR-signaling and YAP have been
reported. Firstly, activation of ERK1/2 is linked to activation with YAP. Depletion of ERK1/2 results in
degradation of YAP, whereas ERK2 overexpression results in YAP rescue. The MEK1/2 inhibitor trametinib
[120]
leads to decrease of YAP levels and decreased HIPPO-signaling . Secondly, in cell lines with increased
resistance against erlotinib, gefitinib or osimertinib, YAP is found in the nucleus (which is a sign of its
[122]
[121]
activation) . Overexpression of YAP leads to increased resistance to erlotinib . YAP expression is also
increased after EGFR-TKI treatment, both in cell line models and human NSCLC samples [123] . Moreover,
activation of YAP leads to an increase in Axl expression and activation and a change to EMT-phenotype of
[123]
the cells . Knock-down of YAP results in resensitization of these cells to EGFR-TKIs. Inhibition of Axl
[123]
activity also resensitizes to EGFR-TKIs .
NF-kB
Recently it was shown that acquired resistance to the novel third-generation EGFR-TKI rociletinib was
mediated by activation of the NF-kB pathway [124] . This study focused on H1975 NSCLC cells, which
harbor a T790M mutation, and are therefore resistant to gefitinib and erlotinib, but sensitive to rociletinib.
Induction of resistance to rociletinib led to NF-kB activation replacing oncogenic EGFR signaling.
Conversely, inhibition of this pathway with the proteasome inhibitor bortezomib sensitized the cells
again to rociletinib. Since bortezomib showed some activity in drug combinations in NSCLC cells
and patients [125-127] , this approach seems promising as an alternative to sensitize patients progressive on
treatment with third-generation EGFR-TKI.

In conclusion, there is a plethora of bypassing pathways to EGFR [Figure 2]. As our knowledge grows,
more bypassing pathways will undoubtedly be discovered.

Resistance mechanisms through histological transformation
A peculiar resistance mechanism to EGFR-TKI is the histological transformation from NSCLC to small
cell lung cancer (SCLC), which occurs in approximately 14% of cases [128] . This has been reported for the
[129]
first time in 2006 by Zakowski et al. . The “transformed” tumor retains the EGFR mutation, but is no
longer responsive to EGFR-TKIs . Although several cases of SCLC have been reported, a lot of questions
[130]
remain on the mechanism and origin of this transformation. However, recent genetic studies [131,132]
revealed that all transformed SCLC have an inactivation of RB1 and TP53 in common. Since the treatment
regimens for NSCLC and SCLC are very different, this raises some questions about the optimal therapy