Repurposing cabozantinib to GISTs: Overcoming multiple imatinib-resistant cKIT mutations including gatekeeper and...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Imatinib is a successful first-line treatment for gastrointestinal stromal tumors (GISTs), but acquired resistance frequently develops due to secondary cKIT kinase mutations.
• Sunitinib and regorafenib are approved for later lines of therapy but have limitations in clinical response, toxicity, and activity against certain resistance mutations.
• There is a significant need for novel therapies effective against a broader spectrum of cKIT mutations in GISTs.

Purpose of the Study:

• To investigate the efficacy of cabozantinib, a drug repositioning candidate, against various cKIT mutations driving GIST.
• To evaluate cabozantinib's potential to overcome resistance to existing therapies like imatinib and sunitinib.
• To provide a preclinical basis for the clinical application of cabozantinib in GIST precision medicine.

Main Methods:

• Drug repositioning approach to identify novel GIST therapies.
• In vitro and in vivo preclinical models using cKIT mutant-driven GIST.
• Assessment of cabozantinib's potency against primary and resistance cKIT mutations, including gatekeeper and activation loop mutants.
• Evaluation of anti-proliferative effects in patient-derived GIST primary cells.

Main Results:

• Cabozantinib demonstrated superior potency compared to imatinib against primary cKIT gain-of-function mutations.
• Cabozantinib effectively overcame imatinib- and sunitinib-resistant cKIT mutations, including the T670I gatekeeper mutation and activation loop mutants.
• Significant in vitro and in vivo efficacy was observed in preclinical GIST models, with a sustained effect post-treatment.
• Dose-dependent anti-proliferative activity was confirmed in primary GIST cells.

Conclusions:

• Cabozantinib exhibits potent activity against a wide range of cKIT mutations relevant to GIST, including those conferring resistance to current therapies.
• The drug demonstrated promising efficacy and a long-lasting effect in preclinical GIST models.
• Cabozantinib's established clinical safety and pharmacokinetic profile support its consideration as an alternative GIST therapy within precision medicine strategies.