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

Abstract

In the majority of gastrointestinal stromal tumors (GIST), oncogenic signaling is driven by KIT mutations. Advanced GIST is treated with tyrosine kinase inhibitors (TKI) such as imatinib. Acquired resistance to TKI is mainly caused by secondary KIT mutations, but can also be attributed to a switch of KIT dependency to another receptor tyrosine kinase (RTK). We tested the efficacy of cabozantinib, a novel TKI targeting KIT, MET, AXL, and vascular endothelial growth factor receptors (VEGFR), in patient-derived xenograft (PDX) models of GIST, carrying different KIT mutations. NMRI nu/nu mice (n ¼ 52) were bilaterally transplanted with human GIST: UZLX-GIST4 (KIT exon 11 mutation, imatinib sensitive), UZLX-GIST2 (KIT exon 9, imatinib dose-dependent resistance), or UZLX-GIST9 (KIT exon 11 and 17 mutations, imatinib resistant). Mice were grouped as control (untreated), imatinib (50 mg/kg/bid), and cabozantinib (30 mg/kg/qd) and treated orally for 15 days. Cabozantinib resulted in significant tumor regression in UZLX-GIST4 and -GIST2 and delayed tumor growth in -GIST9. In all three models, cabozantinib inhibited the proliferative activity, which was completely absent in UZLX-GIST4 and significantly reduced in -GIST2 and -GIST9. Increased apoptotic activity was observed only in UZLX-GIST4. Cabozantinib inhibited the KIT signaling pathway in UZLX-GIST4 and -GIST2. In addition, compared with both control and imatinib, cabozantinib significantly reduced microvessel density in all models. In conclusion, cabozantinib showed antitumor activity in GIST PDX models through inhibition of tumor growth, proliferation, and angiogenesis, in both imatinib-sensitive and imatinib-resistant models. Mol Cancer Ther; 15(12); 2845-52. Ó2016 AACR.

Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors

“…A trend toward a decline of apoptosis was observed with increasing dose of avapritinib. Similar observations were previously reported in this model, where treatments that led to inhibition of KIT signaling resulted in a decrease of apoptotic activity (17,20). This effect could be a consequence of the variable expression of signaling molecules due to specific KIT genotype as reported by several groups (30)(31)(32).…”

“…In this study, we were able to document a robust antitumor activity of avapritinib, a potent and selective KIT inhibitor, in three GIST PDX models characterized by different KIT mutations and varying sensitivity to standard TKI. All three xenografts utilized in this study were previously validated for preclinical testing of novel anti-GIST therapies (17,20).…”

Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors

“…In the current in vivo study, we evaluated the efficacy of plocabulin, a novel cytotoxic tubulin inhibitor, in three PDX models of GIST with different sensitivity to imatinib. All these models have been successfully used in previous in vivo experiments [ 38 , [41] , [42] , [43] ] and retain the morphological, immunohistochemical and molecular features of the original tumors, notwithstanding having been repeatedly passaged. Moreover, the imatinib-treated control groups of the current experiment behaved in a consistent way across the current and earlier experiments performed by our group [ 34 , 40 ].…”

Establishment and Characterization of Histologically and Molecularly Stable Soft-tissue Sarcoma Xenograft Models for Biological Studies and Preclinical Drug Testing

“…Over a period of 93 months, we were able to collect and transplant material from 188 patients with STS, which resulted in the establishment of 32 well-characterized PDX models (XenoSarc platform). This work was based on our xenograft expertise built between 2004 and 2010, a period during which we established a number of mouse models from gastrointestinal stromal tumor, the most common STS of the gastrointestinal tract (26)(27)(28). Our current expanded platform covers models from diverse STS subtypes including some ultrarare entities, all replicating the histologic and molecular features of the donor tissue and maintaining the characteristics throughout passaging.…”