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Ravegnini et al. Cancer Drug Resist 2019;2:107-15 I http://dx.doi.org/10.20517/cdr.2019.02 Page 111

Table 1. Gastrointestinal stromal tumor sensitivity to the approved
tyrosine-kinase inhibitors basing on primary mutational status
Primary mutation IM SU RE
KIT exon 9 S* S S
KIT exon 11 S S S
PDGFRA exon 12 S S U
PDGFRA exon 18 non D842V S S U
PDGFRA exon 18 D842V R R R
*800 mg instead of 400 mg/day. S: Sensitive; R: Resistant; U: Unknown; IM: imatinib; SU: sunitinib; RE: regorafenib

often found in the ATP-binding pocket of the kinase domain (exons 13 and 14) or in the kinase activation
loop (exon 17 and 18) . Despite the acquisition of secondary mutations, delayed resistance may be due
[45]
to different mechanisms, including the KIT overexpression caused by genomic amplification, KIT loss
[45]
of expression with activation of an alternative tyrosine kinase, and ABC transporters overexpression .
Therapeutic management of GIST patients progressed on imatinib consider dose escalation from 400 to
800 mg/day and/or switch to the second and third line TKIs.

The second line sunitinib inhibits several TKRs, blocking multiple biological processes, as tumor growth,
[46]
angiogenesis and metastasis . Sunitinib is effective in imatinib resistant GISTs and it has been shown that
[47]
its activity is affected by the specific primary and secondary mutation . In this context, exon 9 mutant
patients usually have higher clinical benefits and objective response rates, compared with exon 11 mutants.
In addition, both PFS and OS are generally significantly longer in KIT exon 9 mutant or KIT/PDGFRA WT
[47]
GISTs with respect to KIT exon 11 mutant patients . Taking into consideration the acquired mutations,
sunitinib seems to be more effective in case of alterations within KIT exon 13 and 14 (ATP binding pocket)
[47]
rather than those within KIT exon 17 or 18 .
Table 2 shows the correlation between the main secondary KIT mutations and sensitivity to approved TKIs.

SDH deficient GISTs
It is not surprising that KIT/PDGFRA WT GIST show poor response to imatinib and it has been reported that
this GIST subset has a 76% higher risk of death if compared with KIT exon 11 mutants . In this regard, the
[36]
[9]
reports in literature agree in finding a very low benefit for these subsets of GISTs under imatinib treatment .
Furthermore, it seems that KIT/PDGFRA WT-SDH deficient GIST may have better response to sunitinib and
regorafenib [9,48] . Sometimes, metastatic tumors can be quite indolent so that a “wait-and-see” policy applies,
while other patients could benefit from resection. However, considering the complex molecular landscape
of this subset, genetic counseling and therapeutic management plan in a GIST treatment center should be
strongly taken into account.

BRAF/RAS and NF1 mutant GISTs
With regard to BRAF status, in vitro studies showed that alterations on BRAF gene confer imatinib
resistance and, in general, to TKIs including sunitinib, regorafenib and sorafenib [50,51] . It has been proposed
[49]
that this subset of GIST may have benefits from treatment with BRAF inhibitors, as dabrafenib, even if data
are quite limited .
[51]

The data on the prognosis of NF1 mutant GISTs are even more scarce and controversial. A first report
showed a general good overall response in a long term follow-up, with only 5 out of 35 patients who died
due to metastatic disease. On the contrary, two following case reports described NF1 mutant GISTs primary
resistant or only initially responding to imatinib [52-54] . Currently, a Phase II Trial of evaluating MEK1/2
inhibitor, selumetinib, is ongoing for NF1 mutant GIST patients (NCT03109301).