Thursday, May 8, 2014

Imatinib Resistance and GIST

     For our cancer project Braelyn and I will be studying Gastrointestinal Stromal Cancer. James Bradner, the DeNardo lecturer that came to speak to us mentioned this type of cancer and one of its treatments: Gleevac otherwise known as imatinib. One of the most interesting parts of this type of cancer is its high response rate to treatment by the imatinib kinase inhibitor but, this treatment doesn't always work.

     Imatinib acts by occupying the kinase pocket of the BCR-ABL oncoprotein preventing the phosphorylation of its substrate (1). In other words, it is a kinase inhibitor that works to prevent the gain-of-funciton muation of KIT. Imatinib has proven to be a useful treatment of these tumors, however clinical responses to imatinib depended on the exonic location of KIT mutations in GIST (Gastrointestinal Stromal Tumors), and only 10–20% of GIST patients exhibit primary resistance to imatinib (2). It has been found that the actual location of the mutation has a high correlation to the expected response from imatinib treatment (Table 2) (2).

     As seen above, some of these mutations have some to no response to imatinib treatment. In the case of GISTs with KIT exon 9 mutations or no kinase mutations, it is hypothesized that imatinib resistance is due to molecular mutations in the gene itself that are present in the tumors before initiation of therapy. Specifically, these turnouts are thought to have a lesser dependence on KIT signaling for cellular proliferation and avoidance of apoptosis. Therefore, they can more easily adapt to conditions of KIT inhibition (4).  In most cases, of those who have an initial response to the imatinib treatment and then continue with disease progression (secondary resistance), a secondary mutation in KIT (in addition to the primary oncogenic mutation) can be found, usually in the kinase domain, which leads to an imatinib-resistant KIT oncoprotein (2). These secondary mutations are believed to prevent imatinib from binding either by directly altering the pocket itself or by leaving the kinase in a "constantly on" conformation (imatinib can only bind when the kinase is inactive) (3). Sunitinib is a recently approved therapy that is given to patients in this secondary resistance phase. Sunitinib has been shown to prolong survival, but its best response is generally just a stable disease (2).

     It is seen here that imatinib is a good way to treat these types of tumors, but it doesn't always work. Due to the heterogeneous properties of the oncogene(s), the cancer is able to adapt to the presence of imatinib and find new ways to continue to grow. Efforts to manage this secondary stage of tumor growth can be seen with the approval of Sunitinib. This is the best thing out there so far until a new drug can be found to be just as effective as imatinib. But, as we learned on Wednesday, drug development takes a very long time and by the time a drug comes out on the market, many people will have already suffered the ramifications of this rare cancer.

Works Cited:
1. Fletcher, Jonathan A., and Brian P. Rubin. "KIT Mutations in GIST." Current Opinion in Genetics & Development 17.1 (2007): 3-7. Web.
2. Hornick, Jason L., and Christopher D.M. Fletcher. "The Role of KIT in the Management of Patients with Gastrointestinal Stromal Tumors." Human Pathology 38 (2007): 679-87. ELSEVIER. Web.
3.Heinrich, Michael C. "Molecular Basis for Treatment of Gastrointestinal Stromal Tumours." EJC Supplements 4.1 (2006): 10-18. ELSEVIER. Web.
4. Silva, Chandu De, and Robin Reid. "Gastrointestinal Stromal Tumors (GIST): C-kit Mutations, CD117 Expression, Differential Diagnosis and Targeted Cancer Therapy with Imatinib." Pathology Oncology Research 9.1 (2003): 13-19. ELSEVIER. Web.