Abstract

The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drug’s adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.

Highlights

  • IntroductionThe majority of gastrointestinal stromal tumors (GISTs) are driven by a constitutively activating mutation in the KIT or PDGFRA (platelet-derived growth factor receptor alpha) receptor tyrosine kinase

  • The majority of gastrointestinal stromal tumors (GISTs) are driven by a constitutively activating mutation in the KIT or PDGFRA receptor tyrosine kinase

  • Ixazomib and delanzomib have an effect on GIST cell viability and/or apoptosis, imatinib (IM)-sensitive (GIST882, KIT p.K642E; GIST-T1, KIT p.V560_Y578del) and IM-resistant

Read more

Summary

Introduction

The majority of gastrointestinal stromal tumors (GISTs) are driven by a constitutively activating mutation in the KIT or PDGFRA (platelet-derived growth factor receptor alpha) receptor tyrosine kinase. Previous studies from our laboratory have shown that targeting the ubiquitin-proteasome machinery with bortezomib is highly effective in GIST cells[6]. Carfilzomib was approved by the FDA in 2012 for therapy-resistant multiple myeloma and inhibits the β5 chymotrypsin-like subunit of the proteasome, similar to bortezomib, but does so irreversibly and with a higher selectivity[14,15]. Delanzomib reversibly binds the proteasome and can be administered orally and intravenously[19,20] It potently inhibits the β5 chymotrypsin-like and the β1 caspase-like subunit and exhibits a more sustained inhibition of proteasome activity in multiple myeloma cells when compared to bortezomib[19,20]. Results of a phase I/II clinical trial in multiple myeloma were recently reported[21]

Methods
Results
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.