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. While GIST 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. Lastly, 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.

Cabozantinib Is Active against Human Gastrointestinal Stromal Tumor Xenografts Carrying Different KIT Mutations

“…In our models, cabozantinib led to a significant reduction in microvascularization, as assessed by CD31 immunostaining, and the effect was more pronounced than that in imatinib-treated tumors. Similar results were shown previously in Kit V588del/À , which is a genetically modified GIST mouse model (20), but to our knowledge this is the first report of cabozantinib's activity in PDX models of GIST established by immediate transplantation of tumor material. The level of antiangiogenic activity was similar in all three models in our study, suggesting that this effect may be independent of the tumor's molecular background, which may be an important advantage of this compound, as other drugs used in this setting tend to work genotype specific.…”

“…Using several cellular assays and in vivo experiments, Yakes and colleagues have shown the kinase inhibition and antiproliferative effects of cabozantinib in several preclinical solid tumor models (13). In GIST models, cabozantinib demonstrated profound antitumor effects in vivo (20). In our experiments, treatment with cabozantinib resulted in substantial tumor regression in two models with primary KIT mutations, and tumor growth delay in an imatinib-resistant model.…”

“…As a multitargeted kinase inhibitor, cabozantinib can act through blocking several RTKs, including KIT, but also other kinases some authors postulate a potential role in GIST as shown in several preclinical models and patient samples (20,32,33). One of cabozantinib's targets is MET, the tyrosine kinase receptor for hepatocyte growth factor which is implicated in the resistance to different TKIs or monoclonal antibodies in several preclinical models and human tumors (34)(35)(36).…”

“…In GIST, Cohen and colleagues showed that tumor samples from imatinib-resistant tumors can have acquired MET activation. In their study, treatment with MET inhibitors led to enhanced efficacy compared with imatinib in both sensitive and resistant models (20). AXL is another target inhibited by cabozantinib, which is possibly overexpressed in imatinib-resistant tumors, taking over the activity of KIT when inhibited by imatinib ("tyrosine kinase switch" hypothesis; refs.…”

Targeting the HGF/MET Axis Counters Primary Resistance to KIT Inhibition in KIT-Mutant Melanoma

“…30 These data are consistent with those from preclinical studies showing that MET inhibition increases the effect of imatinib in KIT -mutant GIST models. 31 …”