Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors

Noah A. Cohen, Shan Zeng, Adrian M. Seifert, Teresa S. Kim, Eric C. Sorenson, Jonathan B. Greer, Michael J. Beckman, Juan A. Santamaria-Barria, Megan H. Crawley, Benjamin L. Green, Ferdinand Rossi, Peter Besmer, Cristina R. Antonescu, Ronald P. DeMatteo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2061-2070
Number of pages10
JournalCancer Research
Volume75
Issue number10
DOIs
StatePublished - May 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors'. Together they form a unique fingerprint.

  • Cite this

    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. (2015). Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors. Cancer Research, 75(10), 2061-2070. https://doi.org/10.1158/0008-5472.CAN-14-2564