Bosbach, BenediktRossi, FerdinandYozgat, YaseminLoo, JenniferZhang, Jennifer Q.Berrozpe, GeorginaWarpinski, KatherineEhlers, ImkeVeach, DarrenKwok, AndrewManova, KatiaAntonescu, Cristina R.DeMatteo, Ronald P.Besmer, Peter10.07.20192019-07-1010.07.20192019-07-102017Bosbach, B., Rossi, F., Yozgat, Y., Loo, J., Zhang, J. Q., Berrozpe, G. ... Besmer, P. (2017). Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proceedings of the National Academy of Sciences of the United States of America, 114(40), E8448-E8457. https://dx.doi.org/10.1073/pnas.17114491140027-8424https://dx.doi.org/10.1073/pnas.1711449114https://hdl.handle.net/20.500.12511/3705WOS: 000412130500018PubMed ID: 28923937Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic Kit(V558 Delta) mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant Kit(V558 Delta/+) mice, double-mutant Kit(V558 Delta; Y567F/Y567F) knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in Kit(V558 Delta;Y719F/Y719F) mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing Kit(V558 Delta/+) mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinibresistant Kit(V558 Delta;T669I/+) tumors.eninfo:eu-repo/semantics/openAccessGISTKitPI3KMouseArticle11440E8448E845710.1073/pnas.1711449114Q1Q1