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Page 108 Ravegnini et al. Cancer Drug Resist 2019;2:107-15 I http://dx.doi.org/10.20517/cdr.2019.02

from a poor characterized entity, GIST became a paradigm of target therapy. Indeed, at the beginning of
2000, the FDA approved the tyrosine kinase inhibitor (TKI), imatinib, for the management of metastatic
and inoperable GISTs. Imatinib - the magic bullet, originally developed for chronic myeloid leukemia - is the
first example of molecular-targeted drug with a known mechanism of efficacy; it represents the worldwide
[4]
paradigm of targeted therapy specifically tuned vs. specific molecules - peculiar of the cancer cells .

GIST
After the identification of driver genetic events in 1998 and until a few years ago, GISTs were classically
dichotomized in KIT/PDGFRA mutant (about 85%-90%), or KIT/PDGFRA wild-type (WT) GISTs or, often
called, WT GISTs. WT GIST are a small group harboring a plethora of alterations on different genes,
[5,6]
including succinate dehydrogenase (SDH), NF1, BRAF, KRAS . However, with the fast advances in
sequencing technologies, different studies have showed novel genetic mutations in the WT GISTs subgroup.
It became clear that GISTs are a heterogeneous family of tumors, fragmented in different subtypes with
[7,8]
specific and peculiar features , which influence prognosis as well as clinical outcome. In 2014, a report
from NIH suggested to classify GISTs in SDH competent, with characteristics in common with the classic
[9]
KIT/PDGFRA mutant GISTs, and SDH-deficient .
SDH competent GISTs
KIT/PDGFRA mutation
As previously mentioned, the majority of GISTs harbor a mutation in KIT or PDGFRA genes. Specifically,
approximately 80% of GISTs carry pathogenic activating mutations on KIT, whereas 5%-10% harbor PDGFRA
mutations [10,11] . These mutually exclusive mutations are gain of function mutations, leading to a constitutively
and ligand independent activation. This means that the receptors promote the activation of downstream
pathways involved in many key biological processes of carcinogenesis, including RAS/RAF/MEK and PI3K/
AKT/mTOR, and MAPK cascades [12,13] . Genetic alterations in KIT or PDGFRA genes - that can be simple
aminoacid substitutions, in frame deletions or insertions - involve two main regions of the receptors, the
regulatory domains and the enzymatic domains. Considering KIT receptor, the vast part of mutations
(~65%) involve the exon 11, followed by 10% of cases who present a mutation on exon 9. In rare cases (~2%),
primary KIT mutations can also hit exon 13 and exon 17. With regard to PDGFRA, the most common
mutation (~5%) affects the exon 18 at codon 842, and promotes a substitution of an aspartic acid (D) with a
[14]
[14]
valine (V) (D842V) , while mutations on exon 12 and 14 are less frequent . The main difference between
KIT and PDGFRA mutation is the location within the receptor. Indeed, the majority of KIT mutations in
GISTs arise in the juxtamembrane domain (exon 11), but only ~10% of PDGFRA mutations are in this region
(exon 12). On the contrary, alterations within the activation loop of KIT (exon 17) are rare events (< 1%), but
[15]
are prevailing in PDGFRA-mutant GISTs (exon 18) .
BRAF/RAS and NF1 mutant GISTs
Among the SDH competent GISTs are included BRAF/RAS mutant and NF1 mutant GISTs. GISTs with
mutations in BRAF/RAS or NF1 might be referred to as RAS-pathway mutant GISTs. It is estimated that
among patients with no mutations on KIT or PDGFRA (KIT/PDGFRA WT), 5%-13% may have a genetic
alteration on BRAF; in particular, > 90% of BRAF mutations occur in exon 15 on codon 600, usually
V600E [16-18] . The V600E mutation promotes a BRAF activity due to creation of a salt bridge with the residue
K507. V600E-K507 interaction mimics the conformational changes occurring during dimerization, so that
BRAF V600E does not depend on dimerization for increased kinase activity . BRAF is an intracellular
[19]
protein kinase, playing a critical role in the RAS-RAF-MEK-ERK signaling pathway. Mutations on KRAS
are events even more rare than BRAF ones; KRAS mutations in GISTs have a low frequency, spanning from
[16]
~1% to 11% of KIT/PDGFRA WT GIST . Besides the mutations on BRAF/RAS, it has been reported that the
autosomal-dominant inherited disease, neurofibromatosis Type 1 (NF1), promotes an increased incidence of
GIST. In general, about 7% of cases with NF1 mutations will develop a GIST during their lifetime. This type