Scientists found drug repurposing may work in fighting gastrointestinal stromal tumors (GISTs), according to a recent work by a Chinese research team at High Magnetic Field Laboratory of the Chinese Academy of Sciences.

Drug repurposing is an efficient approach that explores new available therapies for the unmet clinical demands. Cabozantinib, described in this work, is a multi-target kinase inhibitor already approved for treating advanced renal cell carcinoma (RCC) and progressive metastatic medullary thyroid cancer (MTC).

But the team demonstrated its significant inhibitory effect in GISTs through their study.

GISTs are the most common mesenchymal malignancies of the gastrointestinal tract and are characterized by the presence of constitutively activated c-KIT. Actually, approximately 75%~85% of GISTs contain activation mutation in the c-KIT proto-oncogene.

For its clinical treatment, imatinib, sunitinib and regorafenib are the approved target therapies..However, due to the multiple drug-acquired resistances, limited clinical response and severe side effects, more effective and safe drugs that can provide different mutation sensitivity spectrum are still highly demanded.

Cabozantinib displayed higher potency than imatinib, the first-line drug in clinics, against primary gain-of-function mutations of c-KIT.

More importantly, it could overcome multiple imatinib-resistant c-KIT secondary mutations and activation loop resistant mutants.

In the mouse models of GISTs, cabozantinib exhibited equal or even better antitumor effects compared with imatinib and sunitinib.

Furthermore, it also showed dose-dependent antiproliferative efficacy in the GISTs patient-derived primary cells harboring both c-KIT wt and mutations.

This work was supported by the National Natural Science Foundation of China and the “Personalized Medicines Molecular Signature-Based Drug Discovery and Development”, Strategic Priority Research Program of the Chinese Academy of Sciences.

Link to the paper: Repurposing cabozantinib to GISTs: Overcoming multiple imatinib-resistant cKIT mutations including gatekeeper and activation loop mutants in GISTs preclinical models

In vitro/vivo effects of cabozantinib against the c-KIT mutant-driven preclinical models of GISTs (Image by the team)

Contact:

ZHOU Shu

Hefei Institutes of Physical Science (http://english.hf.cas.cn/)

Email: zhous@hfcas.ac.cn