TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naive and imatinib-resistant gastrointestinal stromal tumours.

ABSTRACT:

Background

Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT.

Methods

We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines.

Results

TAS-116 inhibited growth and in

SUBMITTER: Saito Y 

PROVIDER: S-EPMC7054534 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature