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 GIST tumors.

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)
Generic Name
Tasigna (AMN107)
35 nmol/L
Most potent
Sutent (SU11248)
245 nmol/L
Sprycel (BMS-354825)
316 nmol/L
Nexavar (BAY 43-9006)
910 nmol/L
Gleevec (STI-571)
3,132 nmol/L
Least potent

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 this table.
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 KIT."