Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors Journal Article

Authors: Cohen, N. A.; Zeng, S.; Seifert, A. M.; Kim, T. S.; Sorenson, E. C.; Greer, J. B.; Beckman, M. J.; Santamaria-Barria, J. A.; Crawley, M. H.; Green, B. L.; Rossi, F.; Besmer, P.; Antonescu, C. R.; DeMatteo, R. P.
Article Title: Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors
Abstract: Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. Although GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops, necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Finally, cabozantinib, a dual MET and KIT small-molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment. © 2015 American Association for Cancer Research.
Keywords: clinical article; controlled study; human tissue; human cell; drug potentiation; nonhuman; drug targeting; mouse; gastrointestinal stromal tumor; imatinib; animal experiment; animal model; rna interference; in vivo study; antineoplastic activity; cancer cell culture; cytotoxicity; in vitro study; tumor xenograft; cell population; oncogene; drug mechanism; upregulation; hypoxemia; drug sensitivity; scatter factor receptor; kit gene; crizotinib; met gene; cabozantinib; human; priority journal; article; cancer cell line
Journal Title: Cancer Research
Volume: 75
Issue: 10
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2015-05-15
Start Page: 2061
End Page: 2070
Language: English
DOI: 10.1158/0008-5472.can-14-2564
PROVIDER: scopus
PMCID: PMC4467991
PUBMED: 25836719
Notes: Export Date: 2 November 2015 -- Source: Scopus
Citation Impact
MSK Authors
  1. Ronald P DeMatteo
    636 DeMatteo
  2. Cristina R Antonescu
    815 Antonescu
  3. Ferdinando Rossi
    23 Rossi
  4. Shan Zeng
    26 Zeng
  5. Peter Besmer
    115 Besmer
  6. Jonathan Bruce Greer
    13 Greer
  7. Teresa Sora Kim
    23 Kim
  8. Megan Hannon Crawley
    12 Crawley
  9. Benjamin Lawrence Green
    10 Green
  10. Noah Avram Cohen
    19 Cohen
  11. Adrian Marcel Seifert
    16 Seifert