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Cancer Res. 2015 May 15;75(10):2061-70. doi: 10.1158/0008-5472.CAN-14-2564. Epub 2015 Apr 2.

Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors.

Author information

1
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. dematter@mskcc.org.

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.

PMID:
25836719
PMCID:
PMC4467991
DOI:
10.1158/0008-5472.CAN-14-2564
[Indexed for MEDLINE]
Free PMC Article

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