Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor

Significance Oncogenic receptor tyrosine kinases (RTKs) are important drug targets in the clinical setting. While RTK inhibitors have become important tools in the clinic, as has been demonstrated with chronic myelogenous leukemia and gastrointestinal stromal tumors (GIST), drug resistance invariably develops. The tools and rationale for the treatment of RTK drug resistance are limited, and success is of short duration. The identification of secondary intracellular drug targets is thus of critical importance. By using new Kit-GIST mouse models in which specific Kit signaling cascades are inhibited, we show the importance of PI3 kinase signaling in tumor development, as well as the utility of PI3 kinase inhibition in the treatment of primary and imatinib-resistant GIST. These studies provide a rationale for targeting dominant molecular pathways in tumors driven by oncogenic kinases.