Two Major Drug Strategies for Wildtype GIST

Two major drug strategies for wildtype GIST

At this time the drug treatment strategies for adult and pediatric wildtype GIST would seem to be the same. The two basic strategies are to inhibit wildtype KIT signaling or to inhibit IGFR-1R signaling. It is unknown which of these strategies will play the more important role in wildtype GIST. There is clinical evidence that inhibiting KIT is beneficial but the evidence of benefit for IGFR-1R is based on test-tube results.

IGF1R in wildtype and pediatric GIST

GISTs without mutations in either of the two genes commonly mutated in GIST typically respond poorly to Gleevec. Andrew Godwin, Ph.D. of Fox Chase Cancer Center and other researchers may have one of the driving forces in these tumors. Dr. Godwin presented his findings at the 2008 American Society of Clinical Oncology (ASCO) meeting in Chicago on Saturday, May 31.

Effective targeted therapies such as Gleevec rely on blocking pathways that are critical to a specific cancer. Gleevec inhibits the aberrant signaling caused by KIT and PDGFRA gene mutations (although some mutations are resistant to Gleevec). KIT mutations are involved in about 75 percent of GISTs and PDGFRA mutations are the driving force in another eight to eleven percent of GISTs. The other ten to 15 percent of GISTs without KIT or PDGFRA mutations are wildtype GISTs.

Mutations that alter a proteins shape and function are one cause of abnormal signaling in cancer cells, but they are not the only cause. Sometimes cancer cells have too much (or too little) of a protein (overexpression). Godwin and his colleagues at Fox Chase have found that (some) wildtype GISTs have extra copies of the insulin-like growth factor 1 receptor (IGF1R) gene and they make way too much of the IGF1R protein.

Two groups; Cristina Antonescu, M.D., and colleagues of Memorial Sloan-Kettering Cancer Center and Godwin and colleagues have both shown that IGF1R is also over expressed in pediatric GIST (another type of “wildtype GIST”). Andrew Wagner and colleagues at Dana Farber Cancer Center and other groups have shown that overexpression of IGF1R seems to be limited to the SDH-deficient GISTs (pediatric-like GISTs).

In 2012, a new clinical trial for an IGF1R inhibitor started. Details can be found at:

Potential new signal pathway in wild-type GIST

Full text article: Insulin-line growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors-Tarn et al., 2008

The role of IGF-1R in Pediatric Malignancies: article by Su Kim, Jeffrey Toretsky, Daniel Scher, Lee Helman

KIT remains an important target

In a paper published in Clinical Cancer Research on May 15, 2008, Dr. Cristina Antonescu reaffirmed her earlier finding that IGF1R was over expressed in pediatric GIST providing additional support for anti-IGR1R therapy for wildtype and pediatric GIST. In addition, Dr. Antonescu tested several of the most popular KIT inhibitors against cells that were engineered to be dependent on wildtype KIT. In this screen of the five most popular KIT inhibitors, Gleevec was found to be the least effective at inhibiting wildtype KIT (see Table). Although the KIT gene is not mutated in wildtype 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 wildtype GISTs or whether some other undiscovered protein will be important.

Approved Drug Name
(IND name, used in trials)

Generic Name
Potency of Approved KIT inhibitors against wildtype KIT

Tasigna (AMN107)
35 nmol/L
Most potent
Sutent (SU11248)
245 nmol/L
blue arrow 
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 indicates more drug was required to inhibit cell proliferation.

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