Presentation Abstract

Abstract Number: A217
Presentation Title: The HSP90 inhibitor, AT13387, demonstrates potent anti-tumor activity in both imatinib-sensitive and imatinib-resistant gastrointestinal stromal tumor models
Location: West Hall, Level One, Moscone Center West
Poster Board Number: A217
Author Block: Tomoko Smyth1, Thomas Van Looy2, Jayne Curry1, Agnieszka Wozniak2, Ana Rodriguez-Lopez1, Patrick Schoffski2, John Lyons1, Neil Thompson1, Nicola Wallis1. 1Astex Pharmaceuticals, Cambridge, United Kingdom; 2Laboratory of Experimental Oncology and Department of General Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
Abstract Body: Background: Activating mutations in the receptor tyrosine kinase, KIT, are found in the majority of gastrointestinal stromal tumors (GIST) and further secondary resistance mutations in KIT frequently arise upon treatment with tyrosine kinase inhibitors such as imatinib. KIT and its mutant forms are sensitive clients of HSP90 and it has been suggested that HSP90 inhibition could be an effective treatment for both imatinib-sensitive and imatinib-resistant GIST, which can occur simultaneously in different clones within the same patient.
Methods: AT13387 is a fragment-derived, potent HSP90 inhibitor, which is currently being evaluated in clinical trials. To evaluate its anti-tumor activity against GIST, AT13387 was tested in both imatinib-sensitive (GIST882, GIST-PSW) and imatinib-resistant (GIST430, GIST48) in vitro and in vivo GIST models.
Results: AT13387 inhibited the proliferation of GIST cell lines at sub-100 nM potencies, irrespective of their sensitivity to imatinib. Treatment of GIST882, GIST430 and GIST48 cells with AT13387 induced HSP70, a marker of HSP90 inhibition, whilst reducing the levels of the client proteins KIT, AKT and their phosphorylated forms. A concomitant decrease in the levels of phospho-ERK and phospho-S6 demonstrated that KIT signalling was being inhibited in all cell lines, whilst an increase in cleaved PARP indicated apoptosis. In contrast, treatment with imatinib inhibited KIT signalling only in the imatinib-sensitive line, GIST882.
In vivo, the efficacy of AT13387 was tested in imatinib-sensitive (GIST-PSW) and imatinib-resistant (GIST430) xenograft models. AT13387, dosed once a week, inhibited the growth of both xenografts; depletion of phospho-KIT and inhibition of KIT signalling were again seen in these tumors. As expected, treatment with imatinib caused significant regression of the GIST-PSW tumors but not of GIST430. The combination of imatinib and AT13387 significantly enhanced tumor growth inhibition (T/C 21%) over either of the monotherapies (T/C 30% for AT13387, 46% for imatinib) in the GIST430 xenograft. Importantly, the combination was well tolerated.
Conclusions: AT13387 is currently being evaluated in a Phase II GIST trial both as single agent and in combination with imatinib. These results support the potential efficacy of the compound in both imatinib-sensitive and imatinib-resistant GIST and its current testing in this disease.

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