KIT remains the primary target of GIST therapy

But a question arises: Did Gleevec inhibit KIT signaling in patients who didn’t respond?

By Angela Riepel and Jerry Call
Life Raft Group Science Team

People get cancer, the theory goes, after a series of molecular missteps within their own cells. Researchers have therefore wondered if a therapy that targets just one molecular misstep in the series would work. The success of Gleevec against chronic myelogenous leukemia (CML), and gastrointestinal stromal tumors (GIST) shows that molecularly targeted therapy can work against these cancers.

The c-Kit gene provides the genetic code for creating the KIT receptor. The KIT receptor belongs to a class of cellular receptors called tyrosine kinase receptors. Mutations in the c-Kit gene (which occurs in most GIST tumors) result in defective KIT receptors in GIST tumors. This results in continuous activation of the KIT receptor (called “constitutive activation”). This activated KIT signaling pathway sends both a proliferation and a survival signal to the GIST tumors through various downstream pathways.

Two recent research papers emphasize the key role the receptor “KIT” plays in sending the signals that trigger GIST tumor growth, and underscore the importance of Gleevec in treating GIST. Gleevec is able to inhibit KIT signaling in GIST, and in doing so, inhibits new cell growth and causes GIST cancer cells to die.

Brian Rubin and colleagues, reporting in “KIT Activation Is a Ubiquitous Feature of Gastrointestinal Stromal Tumors,” that KIT mutations are more common than previously thought, occurring in 92 percent of the tumors examined. Mutations were found in exons 9, 11, 13, and 17 of the KIT gene (exons describe the general location in the gene). Contrary to earlier reports, KIT mutations were also found in each of 10 benign GISTs as well as in borderline and malignant GISTs. This may be because prior studies did not examine as many exons or used different criteria to grade GISTs. Regardless of whether the KIT gene was mutated or not, KIT phosphorylation (indicating activated KIT signaling) was always present. There was no correlation between the mutation’s location and KIT activation. The authors’ conclusion is that KIT activation is a central event in the behavior of GISTs.

In a second paper, “Gastrointestinal Stromal Tumors with KIT Mutations Exhibit a Remarkably Homogeneous Gene Expression Profile” by Susanne Allander and colleagues, 13 KIT-mutant GIST tumors were analyzed using microarray technology. When a gene is “expressed,” it means that is has been activated and is in use by the cell that expresses it. Microarray technology looks at the expression of a large number of genes at the same time. The results showed a remarkably distinct and uniform gene expression profile for all of the GISTs. KIT was found to be the most highly ranked gene on the “discriminator list.” Genes that would be expected to be activated by KIT signaling were also highly expressed.

The striking observation of the microarray study was the remarkable consistency of the gene expression pattern within the GIST tumors (they consistently express the same genes). This high correlation of gene expression is in contrast to that observed in the more common cancers, which show extremely diverse gene expression between tumors.

The authors interpret this observation to suggest that GISTs arise from cells with mutant KIT genes and that the progression from a single cell with a KIT mutation to cancer appears to involve only a limited number of other molecular missteps.

Taken together, the recent literature on GIST underscores the importance of inhibiting KIT signaling when treating GISTs. Even in GISTs where the KIT gene is not mutated (called “wild-type” c-Kit) signaling occurs via the KIT pathway and this may promote proliferation and survival of the cancer cells.

This is supported by the fact that in the phase II trials, more than 50 percent of patients with wild-type c-Kit had either a partial response or stable disease, indicating that inhibiting KIT signaling with Gleevec was important even if the c-Kit gene is not mutated.

In CML patients, treatment failure with Gleevec is associated with failure to inhibit bcr/abl signaling (Gleevec targets bcr/abl signaling, in CML). This leaves us with an interesting question about GIST and Gleevec.
• Was Gleevec able to inhibit KIT signaling in GIST patients who did not respond to Gleevec?

Gleevec will probably remain important for almost all GIST patients (except possibly for those where surgery removed all visible tumors) in the foreseeable future.

For those patients who fail to respond to Gleevec, it is likely that, in the future, another agent or agents will be added to Gleevec to increase its effectiveness. Other drugs might enhance Gleevec’s ability to inhibit KIT activity, inhibit a component of KIT activity such as a downstream pathway, or take advantage of KIT’s inhibition to sensitize tumors to other treatments. Studies examining the expression pattern of genes in GISTs may be used to determine what other molecules those drugs might target.

Another possibility is that other KIT inhibitors may be developed. One such drug in Phase I trials for GIST patients who have failed or are intolerant to Gleevec therapy is Sugen’s SU011248.

The relatively consistent pattern of genes expressed in GISTs suggests that what works for one patient is likely to work for many others. It also presents an opportunity for further study. Since GIST is relatively simple compared to other more complex cancers, it may present a model for study of resistance mechanisms in GIST and other cancers. It also may present a model for studying signaling pathways downstream from KIT. These downstream pathways are likely to be used in other cancers as well, and the relative simplicity of GIST may make them easier to study and develop drugs to affect these downstream targets.

Authors’ note: We are a patient and a caregiver, not doctors. This is offered as well-researched food for thought, and is not a substitute for careful discussion with your doctor.

Sources: “Kit Activation Is a Ubiquitous Feature of Gastrointestinal Stromal Tumors” by Brain P. Rubin, Samuel Singer, Connie Tsao, Anette Duensing, Marcia L. Lux, Robert Ruiz, Michele K. Hibbard, Chang-Jie Chen, Sheng Xiao, David A. Tuveson, George D. Demetri, Christopher D. M. Fletcher, and Jonathan A. Fletcher.

“Gastrointestinal Stromal Tumors with KIT mutations Exhibit a Remarkably Homogeneous Gene Expression Profile” by Susanne V. Allander, Nina N. Nupponen, Markus Ringner, Galen Hostetter, Greg W. Maher, Natalie Goldberger, Yidong Chen, John Carpten, Abdel G. Elkahloun, and Paul S. Meltzer.