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Page 110 Ravegnini et al. Cancer Drug Resist 2019;2:107-15 I http://dx.doi.org/10.20517/cdr.2019.02

With regard to the other KIT/PDGFRA mutant GISTs, the mechanisms of primary resistance is quite
unexpected. However, the most common PDGFRA mutation, D842V, is considered imatinib resistant; this is
due to a conformational change located within the receptor activation loop which makes imatinib unable to
[11]
bind it .
Given the frequency, KIT mutant GIST patients have been studied more extensively than other subtypes.

Mutations on KIT exon 9, accounting for ~10% of GIST cases, are frequently characterized by duplications
of six nucleotides (nt, encoding Ala-Tyr) at position 502-503, located within the extracellular domain. It is
thought that the consequence of this duplication is an alteration in the receptor conformation, which mimics
[8]
the binding of the physiological ligand, the stem cell factor, thus promoting constitutive activation . In
[35]
vitro studies have proven that mutations on KIT exon 9 reduce the sensitivity to imatinib . Furthermore,
presence of exon 9 mutations has been reported as the strongest adverse prognostic factor for imatinib
response, and increases the relative risk of progression and death by 171% and 190% respectively, with respect
[36]
to KIT exon 11 GISTs . Results from different studies have shown that KIT exon 9 GISTs benefit from
higher dose of imatinib, with significantly better progression-free survival (PFS) [35,37,38] . For this reason, this
subset of patients is treated with 800 mg per day of imatinib, (instead of 400 mg), which is now considered
the standard dose for this subgroup. In addition, for metastatic GISTs, it is strongly recommended that the
treatment is continued indefinitely, as it has been observed that treatment outage is usually followed by quick
[24]
tumor progression . ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up
released in 2018, highlight, once again, the importance of biopsy with histological and mutational analyses
to propose the 800 mg imatinib dose for less sensitive KIT exon 9 mutations .
[24]
KIT exon 11 GISTs are those patients who receive greater benefits from imatinib treatment compared with
the other KIT mutational subtypes; indeed, these patients are twice as likely to respond to imatinib. In
addition, KIT exon 11 show also higher response rate in terms of PFS and overall survival (OS). Primary
mutations on KIT exon 13 characterize about 1% of GISTs; these genetic alterations promote changes within
the receptors ATP binding pocket but the functional consequences have not been fully elucidate yet. The
majority of data reported in literature show that mutations on KIT exon 13 confer sensitivity to imatinib,
however a case report has described a rapid and aggressive tumor progression in a patient harboring a
[39]
V654A alteration after imatinib and sunitinib treatment .

With regard to PDGFRA, as mentioned before, carriers of D842V on exon 18 are usually primary resistant.
[15]
PDGFRA D842V represents ~70% of all PDGFRA mutations in GISTs . Besides D842V, patients may harbor
other alterations on exon 18, which can hit close hotspots, as the aminoacids 843 to 845, and commonly
are represented by deletions; in this case, GISTs are sensitive to imatinib. Currently, the largest study so far
conducted, investigating 289 PDGFRA mutant GISTs, showed a variable grade of imatinib sensitivity basing
on the specific mutation . By virtue of these variable responses to imatinib observed in PDGFRA mutant
[40]
GISTs, lately, different PDGFRA inhibitors have been entered into clinical studies. Among those showing
better results, crenolanib was tested in a phase 2 trial and showed important preliminary clinical claims ;
[41]
these data have contributed to the initiation of a phase 3 randomized, placebo-controlled trial of crenolanib
activity in PDGFRA D842V-mutant GISTs (NCT02847429) .
[42]
Table 1 summarizes correlation between exons harboring primary mutations and clinical response [43,44] .

Resistance mutations
As previously anticipated, progression after more than 6 months of initial clinical response is defined as
secondary or acquired resistance. To date, secondary mutations have only been retrieved in patients with
primary KIT mutations and rarely in those with primary PDGFRA mutations. Resistant mutations are most