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Therefore, treatment with a second-generation ALK inhibitor seems to be directly related to a consistently
higher frequency of ALK resistance mutations and to a different range of such ones.

Patients progressing on crizotinib
ALK secondary resistance mutations were detected in 10 (20%) patients, L1196M and G1269A being the most
common, while other minor detected secondary resistance mutations included: G1202R (2%), I1171T (2%),
[33]
C1156Y (2%), S1206Y (2%), and E1210K (2%) .
Patients progressing on ceritinib
More than half of patients progressing on ceritinib (13/24; 54%) presented ALK secondary resistance
mutations, G1202R (21%) and F1174C/L (16.7%) being the most frequent ones, moreover, C1156Y mutations
[33]
were found in the specimens coming from two patients (8%) .
Patients progressing on alectinib
Among 17 repeat biopsies performed on patients progressing on alectinib, ALK secondary resistance
mutations were observed in 9 (53%) specimens, the most common secondary resistance mutation was
G1202R, that was observed in 29% of cases, while other marginally detected mutations included I1171T/S
[33]
(12%), L1196M (6%) and V1180L (6%) .

Patients progressing on brigatinib
ALK secondary resistance mutations were found in 5 of 7 (71%) specimens from patients progressing
on brigatinib. Once again, just like patients progressing on alectinib or ceritinib, G1202R was the most
frequently found ALK secondary resistance mutation, in fact, it was observed in three patients out of
[33]
seven .

Impact of ALK secondary resistance mutations
Therefore, taking these findings into account, while the main mechanism behind acquired resistance to
crizotinib (first generation ALK-TKI) seems to be TKIs pharmacokinetic liability (i.e., resistance occurring
due to continued daily therapy over a long period of time), the development of secondary resistance
mutations (G1202R being the most prominent one) appears to be the primary mechanism accountable for
resistance to and progression after second generation ALK-TKI (ceritinib, alectinib, brigatinib), seemingly
due to the increased selectivity and potency of these drugs [35,36] .

Bypass signaling tracks
In contrast with secondary resistance mutations, the activation of bypass signaling pathways represents
an “off target” resistance mechanism, meaning that tumor cells manage to exploit other RTKs and/or
downstream molecules pathways to overcome ALK dependency in order to keep proliferating despite ALK
inhibition. In fact, this activation can involve transmembrane receptors - most notably EGFR and human
epidermal growth factor receptor family members - as well as downstream molecules: STAT3, TP53, PIK3CA
mutations, MET (MET proto-oncogene, receptor tyrosine kinase) amplification or mitogen-activated protein
kinase reactivation, for example [37-39] .

To date, none of these bypass pathways is targetable.

FUTURE DIRECTIONS
The correct employment of genomic information is key to develop even further personalized precision
cancer therapies.

In fact, third generation ALK-TKI are currently being specifically developed in order to overcome secondary
resistance mutations and more specifically to be effective against G1202R [Table 1]; for example, lorlatinib,