The Response of Imatinib Mesylate in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract, with the most common site in the stomach, followed by the small intestine. GISTs occur most frequently in patients over 50 years of age, although cases have been observed in the pediatric population as well. GISTs are clinically diagnosed by immunohistochemical (IHC) staining of KIT (CD117). Most GISTs mutations are in KIT (about 70%), while a smaller portion are in PDGFRA (10%); these mutations led to the continuous activation of the kinase receptor. The primary treatment for GIST is surgical resection, which is non-curative because of its high rates of recurrence. After being FDA approved in 2002, patients have been prescribed with imatinib mesylate (IM), a small molecule inhibitor designed to fight these tumors by turning off KIT or PDGFRA activity. The patient’s response to IM is in correlation to the genotype of the tumor. GIST patients with exon 11 KIT mutations elicit the best response with disease free-survival, while patients with other KIT mutations and wild-type GIST have a lesser response; the reason being, tumors with 11 KIT mutations have a specific receptor conformation, that is different from other KIT mutations, that allow IM to bind more effectively.

The most effective clinical management of GISTs is to develop individualized treatment approaches based on KIT/PDGFRA mutations; for example, patients with exon 11 KIT would only need a lower dosage of IM, versus patients who have other KIT mutations and the wild type, who would need a higher dosage. While imatinib has been approved to treat GISTs, clinical resistance has become a reality.

The first study of the lab was to determine why some GISTs respond to IM initially, while others are unresponsive, despite the mutational status. The patients used for this study were set up into two groups after a 8-12 week IM treatment: Group A was concluded as responsive to IM (defined as >25 % tumor shrinkage), while Group B was determined as unresponsive (<25 % tumor shrinkage, unchanged or evidence of tumor enlargement). Thirty-two genes were highly expressed from patients that were less responsive to short-term IM treatment. It was concluded that 18 of the 32 IM-sensitizing genes, that mostly included (KRAB)- zinc finger (ZNF), mediate the drug’s activity.

In order to determine how the ZNF’s modulate the response of imatinib, approaches in RNAi were used to turn off the expression of these genes in GISTs cells and assess their effect on gene expression, in order to find a common regulatory pathway. It was concluded that the knockdown of 14- IM sensitizing genes (10 ZNFs), led to the down regulation of 6 genes, including TGFb3, periostin and NEDD9. Overall, the studies implicated that KRAB-ZNFs in modulating the response to TKIs, may be a key mediator in IM sensitivity is GIST.