Abstract
Most gastrointestinal stromal tumors (GISTs) are caused by activating mutations of the KIT receptor tyrosine kinase. The small molecule inhibitor imatinib mesylate was initially developed to target the ABL1 kinase, which is constitutively activated through chromosomal translocation in BCR-ABL1-positive chronic myeloid leukemia. Because of cross-reactivity of imatinib against the KIT kinase, the drug is also successfully used for the treatment of GIST. Although inhibition of KIT clearly has a major role in the therapeutic response of GIST to imatinib, the contribution of concomitant inhibition of ABL in this context has never been explored. We show here that ABL1 is expressed in the majority of GISTs, including human GIST cell lines. Using siRNA-mediated knockdown, we demonstrate that depletion of KIT in conjunction with ABL1 – hence mimicking imatinib treatment – leads to reduced apoptosis induction and attenuated inhibition of cellular proliferation when compared to depletion of KIT alone. These results are explained by an increased activity of the AKT survival kinase, which is mediated by the cyclin-dependent kinase CDK2, likely through direct phosphorylation. Our results highlight that distinct inhibitory properties of targeted agents can impede antitumor effects and hence provide insights for rational drug development. Novel KIT-targeted agents to treat GIST should therefore comprise an increased specificity for KIT while at the same time displaying a reduced ability to inhibit ABL1.
Highlights
Oncogenic mutations in the KIT receptor tyrosine kinase are the tumor-initiating event in the majority of gastrointestinal stromal tumors (GIST) [1]
To determine whether ABL1 is expressed in GISTs, we stained imatinib-sensitive (GIST882, GIST-T1) and imatinib-resistant (GIST430, GIST48, GIST48B) GIST
The majority of gastrointestinal stromal tumors is characterized by oncogenically activating mutations of the KIT receptor tyrosine kinase and can successfully be treated with the KIT inhibitor imatinib mesylate
Summary
Oncogenic mutations in the KIT receptor tyrosine kinase are the tumor-initiating event in the majority of gastrointestinal stromal tumors (GIST) [1]. Imatinib inhibits KIT, and the activity of other tyrosine kinases, most prominently the BCR-ABL1 fusion oncoprotein and the native ABL1 kinase [2,4]. BCR-ABL1 is characterized by constitutive activation of the ABL1 kinase portion of the protein leading to the activation of several intracellular survival pathways. Many of these signaling cascades, such as RAS/RAF/MEK/MAPK and PI3K/AKT/mTOR, are activated by oncogenic KIT in GIST [5, 6]. Inhibition www.impactjournals.com/oncotarget of ABL1 could contribute to the therapeutic effect of imatinib, even when primarily targeting another kinase, such as KIT in GIST
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