Activated KIT remains a target in wild-type and pediatric GIST
The Connective Tissue Oncology Society (CTOS) recently held its 2007 meeting in
Seattle, Washington. At the meeting, Dr. Katherine Janeway, Department of Pediatrics,
Dana-Farber, gave a presentation about Pediatric GIST: "Pediatric KIT and PDGFRA-wildtype
GISTs share KIT activation but not genetic progression mechanisms with adult GISTs".
See ASCO abstract and presentation.
Dr. Janeway and her colleagues reported that, like adult GISTs, the KIT protein
is activated in pediatric GIST despite the fact that KIT rarely is mutated in pediatric
patients. In adults, the KIT protein is mutated over 80 Janewaypercent of the time
and these mutations cause the activation of KIT which is the primary driving force
of adult GIST.
In this study, the patients ranged in age from six to 22 years old at the time of
diagnosis, 85 percent were female, two patients had Carney's Triad and three of
27 (11%) pediatric GIST patients had KIT mutations. The three mutations included
one KIT exon 11, one KIT exon 9 and one PDGFRA exon 18 mutation. Combining these
27 patients with 31 previously published cases, the authors noted that KIT or PDGFRA
mutations are only present in about 15 percent of pediatric GIST cases.
Wild-type is the genetic term used for the typical form of a gene, organism, strain
or characteristic as it was first observed in nature. When someone refers to "wild-type
KIT", it means that the KIT gene is "normal"; it has no detectable mutation. GIST
patients can have mutated KIT (>80% in adults), mutated PDGFRA (about 6-7% in adults)
or they have both wild-type KIT and wild-type PDGFRA (>10% in adults and about 85%
in pediatric GIST). Since it is somewhat clumsy to say that a GIST patient has wild-type
KIT and wild-type PDGFRA, we often shorten this to say a person has "wild-type GIST".
It means that they don't have a mutation in either of the two genes (KIT and PDGFRA)
that typically play the dominant role in GIST.
In this study, 12 of 13 pediatric GIST tumors had activated KIT even though the
KIT protein was not mutated (wild-type). Janeway and her colleagues noted that,
in general, these patients had about the same amount of KIT protein in their tumors
and it was activated as strongly as it is in adults with mutated KIT.
Blocking the growth/survival signal of KIT (or PDGFRA) with Gleevec is the main
treatment for adults with metastatic GIST and it is very effective, at least initially.
A number of different groups have reported that Gleevec is more effective at inhibiting
the most common type of KIT mutations, exon 11 mutations, than to wildtype KIT.
In fact, in test tube experiments, inhibiting wild-type KIT typically requires ten
times the concentration required to inhibit exon 11 KIT (a typical concentration
required to effectively inhibit V560G exon 11 is 0.01- 0.025 µM; for wild-type KIT
it is 0.1- 0.2 µM).
In addition to providing the major driving force in GIST tumors, KIT signaling is
important in a number of normal cell types in the body (for example, the normal
development of blood cells). In patients with exon 11 mutations (most adults and
very few children), the difference in Gleevec sensitivity between the mutant KIT
in tumors and the normal (wild-type) KIT in the rest of the body provides a "therapeutic
window". The goal would be to have a dosage high enough to inhibit the mutant KIT
in tumors, but not so high as to inhibit the (wild-type) KIT signal used by some
normal cells in the body, thereby avoiding unwanted toxicity to normal cells. However,
the difference in sensitivity does raise the question of how well Gleevec is able
to inhibit KIT activation in tumors with wild-type KIT including most pediatric
Sutent (sunitinib) is known to be a potent inhibitor of wild-type KIT and has shown
activity in adult patients with wild-type GIST. Combining this knowledge, along
with the knowledge that KIT was activated in pediatric GIST, Dr. Janeway and her
clinical colleagues have treated six pediatric GIST patients with advanced tumors
that are resistant to imatinib with Sutent. Five of the six patients have had disease
stabilization or a partial response. In four of the five patients the duration of
response was longer than was seen with the previous imatinib treatment. This finding
appears to suggest a possible role for Sutent in pediatric GIST. It also raises
the question of whether other drugs that are potent inhibitors of wild-type KIT
might also have a role in pediatric GIST. Nilotinib and several other KIT inhibitors
are also known to be potent inhibitors of wild-type KIT.
In a paper published in Clinical Cancer Research on May 15, 2008, Dr. Cristina Antonescu
reported results of several of the most popular KIT inhibitors tested against cells
that were engineered to be dependent on wild-type KIT. In this screen of the five
most popular KIT inhibitors, Gleevec was found to be the least effective at inhibiting
wild-type KIT (see Table). Although the KIT gene is not mutated in wild-type GIST,
the KIT protein is known to be strongly activated and to date has still been the
primary target in wildtype GIST, including pediatric GIST. It remains to be seen
whether therapy that targets both KIT and IGF1R will be needed to control wild-type
GISTs or whether some other undiscovered protein will be important.
Potency of Approved KIT inhibitors against wild-type KIT
Approved Drug Name
(IND name, used in trials)
Nexavar (BAY 43-9006)
NOTE: This table is based on in vitro data (lab experiments). This information should
be considered to be preliminary. Response of patients to treatment may vary from
IC50 is the concentration of drug required to inhibit cell proliferation by 50%.
A higher number indications more drug was required to inhibit cell proliferation.
In addition to the central finding that KIT is activated in wild-type pediatric
GIST, the study found that the larger scale genetic changes that typically occur
in adult GIST were rare in the wildtype pediatric GISTs. In adult GIST, KIT mutations
are a very early event in the life of a tumor. These GISTs do not usually become
malignant until other genetic changes occur; specifically the loss or gain of chromosomes
is typical with metastatic GIST. According to Janeway, "...our present findings
show that pediatric malignant GISTs are the first clinically aggressive solid tumor,
in which cytogenetic aberrations, even when queried by high-resolution SNP assays,
are undetectable in most cases." She summarized, "Our findings suggest that pediatric
GISTs are biologically distinct from adult GISTs and that targeted therapies for
pediatric GIST should focus on inhibitors of KIT activation or signaling molecules
downstream of KIT with an emphasis on those agents that strongly inhibit wild-type