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

Authors: Bosbach, B.; Rossi, F.; Yozgat, Y.; Loo, J.; Zhang, J. Q.; Berrozpe, G.; Warpinski, K.; Ehlers, I.; Veach, D.; Kwok, A.; Manova, K.; Antonescu, C. R.; DeMatteo, R. P.; Besmer, P.
Article Title: Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor
Abstract: Gastrointestinal 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 KitV558Δ mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant KitV558Δ/+ mice, double-mutant KitV558Δ;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 KitV558Δ;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 KitV558Δ/+ 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 imatinib-resistant KitV558Δ;T669I/+ tumors. © 2017, National Academy of Sciences. All rights reserved.
Keywords: mouse; kit; gist; pi3k
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 114
Issue: 40
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2017-10-03
Start Page: E8448
End Page: E8457
Language: English
DOI: 10.1073/pnas.1711449114
PROVIDER: scopus
PMCID: PMC5635919
PUBMED: 28923937
Notes: Ferdinando Rossi's name is misspelled on the original publication -- Article -- Export Date: 2 November 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Ronald P DeMatteo
    635 DeMatteo
  2. Darren Veach
    77 Veach
  3. Cristina R Antonescu
    761 Antonescu
  4. Ferdinando Rossi
    23 Rossi
  5. Peter Besmer
    114 Besmer
  6. Yasemin Yozgat
    4 Yozgat
  7. Imke Ehlers
    4 Ehlers
  8. Benedikt Bosbach
    10 Bosbach
  9. Jennifer Qi Zhang
    21 Zhang
  10. Jennifer Loo
    13 Loo