Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells.

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 theref

SUBMITTER: Rausch JL 

PROVIDER: S-EPMC7083865 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature