Reference Detail

Ref Type

Journal Article

PMID

(27777285)

Authors

Gebreyohannes YK, Schöffski P, Van Looy T, Wellens J, Vreys L, Cornillie J, Vanleeuw U, Aftab DT, Debiec-Rychter M, Sciot R, Wozniak A

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	12	2016 Dec	2845-2852	Mol Cancer Ther

URL

Abstract Text

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 = 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. ©2016 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT K558_G565delinsR	gastrointestinal stromal tumor	sensitive	Imatinib	Preclinical - Pdx	Actionable	In a preclinical study, Gleevec (imatinib) treatment resulted in tumor regression and decreased mitotic activity in gastrointestinal stromal tumor patient derived xenograft (PDX) models harboring KIT K558_G565delinsR (PMID: 27777285).	27777285
KIT K558_G565delinsR	gastrointestinal stromal tumor	sensitive	Cabozantinib	Preclinical - Pdx	Actionable	In a preclinical study, Cometriq (Cabometyx, cabozantinib) treatment resulted in tumor regression, decreased mitotic activity, and increased apoptotic activity in a gastrointestinal stromal tumor patient-derived xenograft (PDX) model harboring KIT K558_G565delinsR (PMID: 27777285).	27777285
KIT A502_Y503dup	gastrointestinal stromal tumor	conflicting	Imatinib	Preclinical - Pdx	Actionable	In a preclinical study, a gastrointestinal stromal tumor patient-derived xenograft (PDX) model harboring KIT A502_Y503dup demonstrated resistance to treatment with Gleevec (imatinib), resulting in increased tumor volume (PMID: 27777285).	27777285
KIT A502_Y503dup	gastrointestinal stromal tumor	sensitive	Cabozantinib	Preclinical - Pdx	Actionable	In a preclinical study, Cometriq (Cabometyx, cabozantinib) resulted in decreased tumor volume and reduced mitotic activity in a gastrointestinal stromal tumor patient derived xenograft (PDX) model harboring KIT A502_Y503dup (PMID: 27777285).	27777285
KIT W557Lfs*5 KIT P577del KIT D820G	gastrointestinal stromal tumor	sensitive	Cabozantinib	Preclinical - Pdx	Actionable	In a preclinical study, Cometriq (Cabometyx, cabozantinib) slowed tumor growth and decreased mitotic activity in a gastrointestinal stromal tumor patient-derived xenograft (PDX) model harboring KIT P577del, KIT W557Lfs*5, and KIT D820G (PMID: 27777285).	27777285
KIT W557Lfs*5 KIT P577del KIT D820G	gastrointestinal stromal tumor	resistant	Imatinib	Preclinical - Pdx	Actionable	In a preclinical study, a gastrointestinal stromal tumor patient-derived xenograft (PDX) model harboring KIT P577del, KIT W557Lfs*5, and KIT D820G demonstrated resistance to treatment with Gleevec (imatinib) (PMID: 27777285).	27777285