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compounds. This can be experimentally validated by determining the intracellular concentration of these
compounds with and without the addition of Bafilomycin A1 [146,147] . Bafilomycin A1 is a proton pump
inhibitor that causes a disruption in the lysosomal pH, thus eliminating the pH gradient between the
cytoplasm and the lysosomes. This prevents the protonation of the compounds and causes a decreased
intracellular drug concentration.

Lysosomal trapping has been identified as a resistance mechanism against anticancer drugs by shielding
the respective targets from the drugs [148,149] . Furthermore, this drug accumulation causes lysosomal
stress, resulting in the activation of the coordinated lysosomal expression and regulation-pathway by
[145]
[150]
transcription factor EB and in lysosomal exocytosis .
Focusing on the EGFR-TKIs: erlotinib does not accumulate in the lysosomes by lysosomal sequestration [134] ,
gefitinib on the other hand is a lysosomotropic compound [143] . As mentioned above gefitinib’s uptake is
[151]
mediated by an active process and subsequently the drug seems to be trapped in the cells . In contrast,
erlotinib is likely to be transported into the membrane, binds to the target and is effluxed before entering
the cell . For the second- and third-generation EGFR-TKIs, this needs to be assessed.
[151]

Future directions
The ultimate goal of every anticancer treatment is to cure cancer, by delaying disease progression and
providing a longer overall survival. Unfortunately, in the case of advanced NSCLC, despite the giant steps
that have been made in the last decade, a definitive cure is still far from being discovered. The majority of
the NSCLC patients lack a targetable driving mutation, and in this case they could be treated with immune
checkpoint inhibitors or combinations of cytotoxic drugs, such as gemcitabine-cisplatin (or carboplatin),
gemcitabine and a taxane, a taxane and cisplatin (or carboplatin), pemetrexed and cisplatin (for non-
squamous NSCLC) [1,152] . Although these combinations have been extended with TKIs, the approach was
usually not successful. Therefore, concerning EGFR-mutated NSCLC, a current challenge is to stay ahead
of resistance against EGFR-TKIs.

A first strategy is to simultaneously inhibit multiple signaling pathways with combination therapy, such
as a dual inhibition of EGFR and cMET signaling. This can prevent the activation of the bypassing cMET
pathway upon EGFR inhibition and thus block a possible way-out for the cancer cells. However, given the
multiple possible escape strategies, it remains a big challenge to predict the future mechanism of resistance
of a specific tumor and target it from the beginning. Moreover, in order to be able to determine the
acquired mechanism of resistance, continuous research is needed. Once a novel mechanism of resistance
is discovered it is necessary to expand the screening strategies in clinical routine to bring it to the patients.
However, sometimes the discovered mechanism of resistance is not fully targetable. A good example is the
occurrence of mutations in KRAS: although extensive research has been conducted into Ras-inhibitors, no
suitable drug is available to date.

A second strategy is a combination with immunotherapy, although an extensive discussion of these
combinations is beyond the scope of this paper. In NSCLC, immunotherapy seems most effective in
patients with a high tumor load, but all predictive parameters are still under investigation and need to be
validated. A remaining question will be whether immunotherapy should be given before treatment with
a TKI or whether the TKI should be given until resistance and then be followed with immunotherapy .
[153]
Alternatively, TKIs might be combined with immunotherapy, but this approach is in its infancy.
However, certain types of therapy, including standard chemotherapy and some TKIs can induce synthesis
and excretion of several cytokines and chemokines, which play an important role in the efficacy of
immunother