Abstract
Gastrointestinal stromal tumors (GIST) can be successfully treated with imatinib mesylate (Gleevec); however, complete remissions are rare and patients frequently achieve disease stabilization in the presence of residual tumor masses. The clinical observation that discontinuation of treatment can lead to tumor progression suggests that residual tumor cells are, in fact, quiescent and, therefore, able to re-enter the cell-division cycle. In line with this notion, we have previously shown that imatinib induces GIST cell quiescence in vitro through the APC(CDH1)-SKP2-p27(Kip1) signaling axis. Here, we provide evidence that imatinib induces GIST cell quiescence in vivo and that this process also involves the DREAM complex, a multisubunit complex that has recently been identified as an additional key regulator of quiescence. Importantly, inhibition of DREAM complex formation by depletion of the DREAM regulatory kinase DYRK1A or its target LIN52 was found to enhance imatinib-induced cell death. Our results show that imatinib induces apoptosis in a fraction of GIST cells while, at the same time, a subset of cells undergoes quiescence involving the DREAM complex. Inhibition of this process enhances imatinib-induced apoptosis, which opens the opportunity for future therapeutic interventions to target the DREAM complex for more efficient imatinib responses.
Highlights
The majority of gastrointestinal stromal tumors (GIST), the most common mesenchymal tumor of the gastrointestinal tract, are characterized by oncogenic mutations in the KIT or platelet-derived growth factor receptor-a (PDGFRA) receptor tyrosine kinase [1,2,3]
Imatinib treatment led to a significant increase of tumor cells exhibiting nuclear p27Kip1 staining in GIST882 xenografts (Fig. 1A) and patient-derived xenografts carrying a mutation in KIT exon 11 (Fig. 1B) thereby confirming the ability of imatinib to induce quiescence in Gastrointestinal stromal tumors (GIST) cells in vivo
In line with clinical observations, we find that drug removal leads to reactivation of cellular proliferation, yet does not affect the sensitivity of GIST cells when rechallenged with imatinib
Summary
The majority of gastrointestinal stromal tumors (GIST), the most common mesenchymal tumor of the gastrointestinal tract, are characterized by oncogenic mutations in the KIT or platelet-derived growth factor receptor-a (PDGFRA) receptor tyrosine kinase [1,2,3] Because these oncogenic mutations lead to constitutive, ligand-independent activation of the receptor, GISTs can be successfully treated with the small-molecule kinase inhibitor imatinib mesylate Successful cancer therapy is often hampered by the occurrence of tumor cell quiescence, because quiescent cells remain viable and, are a reservoir for tumor progression [6,7,8] This reversible exit from the cell division cycle and entry into G0 has previously been shown to involve the anaphase-promoting complex (APC)CDH1–SKP2–p27Kip signaling axis [9,10,11,12,13]. We could show that this process is active in imatinib-treated GIST cells [14]
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