Pimitespib effectively inhibits in vivo tumor progression in a mouse model of gastrointestinal stromal tumor (GIST) with a germline KIT-Asp818Tyr mutation, according to a new study published in Experimental and Molecular Pathology. This result suggests that pimitespib might also control the progression of multiple GISTs in patients with germline KIT-Asp820Tyr mutations. 

“Although careful observation may be necessary in case of pimitespib treatment for the patients of multiple GIST families with KIT-Asp820Tyr, we expect that pimitespib can control the progression of multiple GISTs of them,” the authors of the study wrote.

Pimitespib is a novel, orally active selective inhibitor of heat shock protein (HSP) 90. Previous research in a human non-small cell lung cancer xenograft rat model has shown that it has antitumor activity without detectable ocular toxicities. It has also been shown to inhibit both the in vitro proliferation of cultured GIST cells with mutant KIT and the growth of GIST xenografts with mutant KIT. Finally, results of a phase 2 clinical trial in patients with GIST showed that pimitespib treatment led to a median progression-free survival of 4.4 months.

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Most GISTs express a receptor tyrosine kinase, KIT, encoded by the proto-oncogene c-kit, and there is a somatic mutation in the c-kit gene in the majority of sporadic GISTs. 

Read more about GIST etiology

Previous research reported 3 families with multiple GISTs caused by a germline Asp820Tyr mutation in the c-kit gene, leading to an aspartate to tyrosine substitution at position 820 in the KIT protein (KIT-Asp820Tyr).

Here, researchers from Japan assessed the effect of pimitespib in inhibiting the phosphorylation of KIT-Asp818Tyr using a mouse model with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr that they generated previously. They also investigated whether the drug could decrease the cecal tumor volume.

The results showed that pimitespib indeed inhibited KIT phosphorylation in culture cells and in the model mice with KIT-Asp818Tyr. Orally administered pimitespib also led to significantly smaller cecal tumor volume in heterozygous KIT-Asp818Tyr mice compared to those treated with vehicle only. Moreover, the activation of KIT signaling molecules was strongly inhibited in the tumor tissues of mice treated with pimitespib compared to those of control animals.

These findings suggest that pimitespib inhibits the progression of GIST in patients with germline KIT-Asp820Tyr mutations.


Kihara T, Yuan J, Watabe T, et al. Pimitespib is effective on cecal GIST in a mouse model of familial GISTs with KIT-Asp820Tyr mutation through KIT signaling inhibition. Exp Mol Pathol. Published online October 1, 2021. doi:10.1016/j.yexmp.2021.104692