Salient features of GIST tumor cells are their expression of the Kit receptor tyrosine kinase and the fact that in amajority of GIST, the Kit receptor harbors an oncogenic mutation. Kit is a membrane molecule which resides on the surface of cells and consists of an extra-cellular domain (Outside the membrane), a transmembrane domain (Passes through the membrane), and an intracellular domain (Inside the membrane), carrying a protein kinase that phosphorylates tyrosine residues on substrate proteins.

In normal cells, Kit ligand/stem cell factor binds to the extracellular domain of Kit and activates the Kit protein kinase. Ligand mediated activation of Kit sets in motion distinct signaling cascades, including the phosphatidyl inositide 3-kinase cascade, the Ras MAP kinase cascade, Src family kinase signaling and signaling by Stat transcription factors.

Kit is expressed and functions in several distinct cell types in the body, yet in these different cell types the intracellular machinery available to transmit signals from the Kit receptor may vary. Therefore, in different cell types the consequences of Kit receptor signaling are distinct.

In the gut Kit is expressed in pacemaker cells, “Interstitial Cells of Cajal”, which are responsible for normal gut movement. Lack of Kit in these cells results in the disappearance of these pacemaker cells and impaired gut movement. Thus Kit is a critical signaling entity in the pacemaker cells of the gut. It is believed that an oncogenic mutation in the Kit receptor in these pacemaker cells first produces hyperplasia and eventually after acquisition of more mutations, malignant GIST.

Therefore, oncogenic/constitutive Kit receptor signaling appears to be critical in GIST, in the development of the tumor as well as in the proliferation and survival of GIST tumor cells.

In agreement with the notion that Kit signaling has a critical role in tumor maintenance, the tyrosine kinase inhibitor, Gleevec, which blocks Kit receptor function as well as a few related tyrosine kinases, is being used with great success to treat a majority of patients with GIST. However, most of the time Gleevec treatment results in a partial response or stable disease. Clearly some tumor cells survive, but their proliferation is impaired. This could indicate on one hand that inhibition of oncogenic Kit is incomplete, or that other signaling mechanisms may compensate for the loss of Kit signaling. Improving therapeutic outcome in treating GIST patients remains a great challenge. A prerequisite for this is a detailed understanding of how Kit transmits its signals intracellularly to mediate its function in tumor cells as well as the identification of compensatory signaling mechanisms in tumor cells originating either from other receptors or from the extracellular matrix.

One approach for improving clinical efficacy is to develop drugs which are better inhibitors of Kit and or which have broader activity; this means that they inhibit Kit as well as other receptor kinases. An example of this second category would be Sutent, which is in use in Gleevec-resistant patients.

A second approach is to identify intracellular molecules which are critical in mediating Kit function and to develop inhibitors against them. Cellular processes such as cell proliferation and cell survival are produced by complex signaling networks emanating from several input signals. Thus, critical signaling pathways may be used by Kit as well as the elusive parallel receptor signaling pathways and therefore inhibition of intracellular signaling molecules in combination with Kit receptor inhibitors could be effective in inhibiting multiple signaling cascades at once.

Improved treatment strategies for GIST may require the use of multiple drugs simultaneously, but working out and fine tuning such cocktail approaches will take time. Important tools in such preclinical investigations will be the GIST mouse models that have been developed in the recent past by the LRG Research Team and other doctors.

Written by Peter Besmer, M.D.

LRG Contributor
Author: LRG Contributor