The HSP90 inhibitor, AT13387, is effective against imatinib-sensitive and -resistant gastrointestinal stromal tumor models.

Abstract

The majority of gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT, an HSP90 client protein. Further secondary resistance mutations within KIT limit clinical responses to tyrosine kinase inhibitors, such as imatinib. The dependence of KIT and its mutated forms on HSP90 suggests that HSP90 inhibition might be a valuable treatment option for GIST, which would be equally effective on imatinib-sensitive and -resistant clones. We investigated the activity of AT13387, a potent HSP90 inhibitor currently being evaluated in clinical trials, in both in vitro and in vivo GIST models. AT13387 inhibited the proliferation of imatinib-sensitive (GIST882, GIST-T1) and -resistant (GIST430, GIST48) cell lines, including those resistant to the geldanamycin analogue HSP90 inhibitor, 17-AAG. Treatment with AT13387 resulted in depletion of HSP90 client proteins, KIT and AKT, along with their phospho-forms in imatinib-sensitive and -resistant cell lines, irrespective of KIT mutation. KIT signaling was ablated, whereas HSP70, a marker of HSP90 inhibition, was induced. In vivo, antitumor activity of AT13387 was showed in both the imatinib-sensitive, GIST-PSW, xenograft model and a newly characterized imatinib-resistant, GIST430, xenograft model. Induction of HSP70, depletion of phospho-KIT and inhibition of KIT signaling were seen in tumors from both models after treatment with AT13387. A combination of imatinib and AT13387 treatment in the imatinib-resistant GIST430 model significantly enhanced tumor growth inhibition over either of the monotherapies. Importantly, the combination of AT13387 and imatinib was well tolerated. These results suggest AT13387 is an excellent candidate for clinical testing in GIST in combination with imatinib.

• Authors: Tomoko Smyth, Thomas Van Looy, Jayne E Curry, Ana M Rodriguez-Lopez, Agnieszka Wozniak, Meijun Zhu, Rachel Donsky, Jennifer G Morgan, Mark Mayeda, Jonathan A Fletcher, Patrick Schöffski, John Lyons, Neil T Thompson, Nicola G Wallis
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 8 Pg. 1799-808 (Aug 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22714264 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• HSP90 Heat-Shock Proteins
• Isoindoles
• Piperazines
• Pyrimidines
• Imatinib Mesylate
• Proto-Oncogene Proteins c-kit
• (2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Benzamides (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Gastrointestinal Stromal Tumors (drug therapy, metabolism)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Imatinib Mesylate
• Isoindoles (administration & dosage, pharmacology)
• Mice
• Mice, SCID
• Piperazines (pharmacology)
• Proto-Oncogene Proteins c-kit (metabolism)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays