Imatinib Resistance Mechanisms in GIST

This proposal seeks to enable therapeutic advances in oncology by characterizing resistance mechanisms to receptor tyrosine kinase-inhibition in gastrointestinal stromal tumor (GIST). The recent advent of biologically rational therapies for GIST is one of the more compelling developments in solid tumor oncology. Such therapies target activated forms of the KIT and PDGFRA receptor tyrosine kinases, which are critical transforming oncoproteins in more than 90% of GISTs. GISTs were formerly viewed as the most treatment-refractory sarcomas, with fewer than 10% of patients showing clinical response to conventional chemotherapies or radiation therapy. Metastatic GIST was a rapidly progressive disease, average survival being less than one year. However, the initial clinical experience with the KIT/PDGFRA inhibitor, imatinib mesylate (Gleevec), has been dramatic, with at least 50% of patients having major clinical responses. Many of these therapeutic responses have been sustained for the three years since Gleevec was first given to GIST patients. Despite the remarkable clinical responses to tyrosine kinase inhibition, we are seeing relapses of GIST, even in patients for whom the initial response to Gleevec was spectacular. Therefore, the aim of the proposed research is to characterize Gleevec resistance mechanisms in GISTs, and to identify therapeutic strategies that circumvent Gleevec resistance. This aim will be accomplished by evaluating the heterogeneity of Gleevec resistance mechanisms within and between different metastatic GIST lesions in each patient. Biochemical and genomic studies will be performed to identify targeted therapies that synergize with Gleevec in destroying the GIST cells. A key advantage in the GIST model is that the mutant kinase oncoprotein targets of Gleevec can be identified readily in most patients. This starting point assures rapid progress in determining essential oncogenic signaling pathways, and novel therapeutic targets, in patients with Gleevec- resistant GIST. The aim of these translational studies is to translate the mechanistic understanding of Gleevec resistance into improved medical therapy for patients whose GISTs are progressing on Gleevec therapy. The overarching aim of this work- and therefore the broader relevance to the field of cancer research - is to provide molecular insights which will anticipate mechanisms of targeted therapy resistance in other solid tumors.