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

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Gastrointestinal stromal tumors (GIST) are often driven by KIT mutations, with imatinib being a primary treatment.
• Acquired resistance to imatinib in GIST can arise from secondary KIT mutations or altered receptor tyrosine kinase (RTK) dependency.

Purpose of the Study:

• To evaluate the efficacy of cabozantinib, a multi-targeted tyrosine kinase inhibitor (TKI), in patient-derived xenograft (PDX) models of GIST with various KIT mutations.
• To assess cabozantinib's impact on tumor growth, proliferation, apoptosis, signaling pathways, and angiogenesis in imatinib-sensitive and resistant GIST models.

Main Methods:

• Utilized three human GIST PDX models (UZLX-GIST4, -GIST2, -GIST9) with distinct KIT mutations and imatinib sensitivities, engrafted in NMRI nu/nu mice.
• Administered cabozantinib (30 mg/kg/qd) or imatinib (50 mg/kg/bid) orally for 15 days, with untreated control groups.
• Assessed tumor regression, growth delay, proliferation (Ki67), apoptosis, KIT signaling inhibition, and microvessel density.

Main Results:

• Cabozantinib induced significant tumor regression in imatinib-sensitive (UZLX-GIST4) and dose-dependent resistant (UZLX-GIST2) models, and delayed growth in imatinib-resistant (UZLX-GIST9) models.
• Cabozantinib markedly inhibited tumor cell proliferation across all models and induced apoptosis in UZLX-GIST4.
• Inhibition of KIT signaling was observed in UZLX-GIST4 and -GIST2, and cabozantinib significantly reduced microvessel density in all tested GIST models.

Conclusions:

• Cabozantinib exhibits significant antitumor activity in GIST PDX models, targeting tumor growth, proliferation, and angiogenesis.
• The drug demonstrates efficacy in both imatinib-sensitive and imatinib-resistant GIST, suggesting potential for treating advanced or refractory disease.
• Cabozantinib's multi-targeting profile, including KIT, MET, AXL, and VEGFR, contributes to its broad anti-GIST activity.