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Page 240 Van Der Steen et al. Cancer Drug Resist 2018;1:230-49 I http://dx.doi.org/10.20517/cdr.2018.13

in the occurrence of a histological transformation. Four patients with a SCLC transformation were
switched to a SCLC-oriented platinum-etoposide chemotherapy, which produced marked responses in
[128]
three patients . Moreover, case reports show good results from “drug-holidays”. For example, a patient
originally presenting with an L858R positive adenocarcinoma showed a good initial response to erlotinib.
When resistance occurred, a rebiopsy showed a SCLC subtype containing both an L858R and a PIK3CA
mutation. This SCLC was resistant to erlotinib. After a couple of months without any EGFR-TKI the
tumor had switched back to the adenocarcinoma subtype, retained the L858R mutation but the PIK3CA
mutation could not be detected anymore. After a couple of months of response to erlotinib, the patient
became resistant again, and rebiopsy showed again the SCLC subtype with both an L858R and PIK3CA
[128]
mutation .
Resistance through aberrations in drug transporters
Several families of drug transporters are currently known which may play a role in resistance to EGFR
inhibitors in NSCLC [133,134] . Examples are the organic anion transporters, organic cation transporters (OCT),
organic anion transporting polypeptides, equilibrative nucleoside transporters and the ABC-transporter
superfamily which contains the Breast Cancer Resistance Protein (BCRP), P-glycoprotein (PGP) and
[134]
multidrug resistance protein (MRP) family . Gefitinib uptake seems mediated by an OCT and the uptake
of erlotinib seems to have a mixed pattern, active and passive. However, literature is not consistent because
of the great diversity of drug transporters and their functions on TKIs.

Erlotinib and gefitinib both have been shown to interact with ABCB1/PGP and ABCG2/BCRP; one
[135]
interesting aspect is their role on trafficking of the transporters, affecting their function . The influence
of these efflux pumps has been studied most extensively in relation to gefitinib. Gefitinib acts both as
a substrate and as an inhibitor of these pumps. Hereby, the concentration of gefitinib is important. At
low concentrations (IC values in nmol/L range) gefitinib activates BCRP-ATPase activity in cell lines,
50
whereas at concentrations > 1 µmol/L this stimulatory effect is lower [136,137] . Transduction of BCRP in
gefitinib sensitive cell lines in the nanomolar range lead to gefitinib resistance. The BCRP-inhibitor Ko143
could reverse this resistance. However, this effect was much less in cell lines that are relatively insensitive
[138]
to gefitinib (IC values in µmol/L range) . Due to its role as a BCRP-inhibitor, gefitinib is also able to
50
overcome BCRP-mediated resistance in vitro [138,139] .
Erlotinib and efflux pumps are studied less well. Erlotinib is a target of PGP and BCRP, but not of
-/-
MRP2 [140] . In the triple knock-out mouse (BCRP1/MDR1a/MDR1b ), the oral bioavailability of erlotinib
was increased with 66%, which led to increased systemic exposure to erlotinib [140] , but in cell lines
overexpressing BCRP the sensitivity to erlotinib could not be increased by specific inhibitors of BCRP such
as Ko143, questioning the role of BCRP .
[141]
Afatinib is both a substrate and inhibitor for the efflux pumps PGP and BCRP, however, the therapeutic
doses of afatinib are too low to affect the function of these pumps in vivo [142] .

Lysosomal sequestration
Lipophilic or amphiphilic compounds can undergo a process called lysosomal sequestration,
[143]
[144]
lysosomotropism or acid trapping . These compounds are characterized by a pKa between 6.5 and 11 .
Due to this pKa the compounds are neutral in the cytosol, which has a pH of around 7.2-7.4, and can
diffuse passively through the membranes. When crossing the membrane of the lysosomes, the pH lowers
to around 4.5-5. Hereby the compounds become protonated in the lysosomes and can no longer diffuse
[145]
through the membranes and become “trapped” in the lysosomes .

[134]
A study of the physicochemical properties of TKIs showed that several TKIs function as lysosomotropic