Pimitespib is effective on cecal GIST in a mouse model of familial GISTs with KIT-Asp820Tyr mutation through KIT signaling inhibition.

Three families with multiple gastrointestinal stromal tumors (GISTs) caused by a germline Asp820Tyr mutation at exon 17 of the c-kit gene (KIT-Asp820Tyr) have been reported. We previously generated a knock-in mouse model of the family, and the mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal tumor equivalent to human GIST. In the model mice, we reported that tyrosine kinase inhibitor, imatinib, could stabilize but not decrease the cecal tumor volume. In this report, we examined whether a heat shock protein 90 inhibitor, pimitespib (TAS-116), has an inhibitory effect on phosphorylation of KIT-Asp818Tyr and can decrease the cecal tumor volume in the model mice. First, we showed that pimitespib inhibited KIT phosphorylation both dose- and time-dependently in KIT-Asp818Tyr transfected murine Ba/F3 cells. Then, four 1-week courses of pimitespib were orally administered to heterozygous (KIT-Asp818Tyr/+) model mice. Each course consisted of once-daily administration for consecutive 5 days followed by 2 days-off. Cecal tumors were dissected, and tumor volume was histologically analyzed, Ki-67 labeling index was immunohistochemically examined, and apoptotic figures were counted. Compared to the vehicle treated mice, pimitespib administered mice showed statistically significantly smaller cecal tumor volume, lower Ki-67 labeling index, and higher number of apoptotic figures in 10 high power fields (P = 0.0344, P = 0.0019 and P = 0.0269, respectively). Western blotting revealed that activation of KIT signaling molecules was strongly inhibited in the tumor tissues of pimitespib-administered mice compared to control mice. Thus, pimitespib seemed to inhibit in vivo tumor progression effectively in the model mice. These results suggest that the progression of multiple GISTs in patients with germline KIT-Asp820Tyr might be controllable by pimitespib.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)