title: The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis.
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.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Boichuk
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Parry
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Makielski
authors.forename: Larisa
authors.initials: L
authors.lastname: Litovchick
authors.forename: Julianne L
authors.initials: JL
authors.lastname: Baron
authors.forename: James P
authors.initials: JP
authors.lastname: Zewe
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Keith R
authors.initials: KR
authors.lastname: Mehalek
authors.forename: Nina
authors.initials: N
authors.lastname: Korzeniewski
authors.forename: Danushka S
authors.initials: DS
authors.lastname: Seneviratne
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
authors.forename: Anette
authors.initials: A
authors.lastname: Duensing
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D051605:Kv Channel-Interacting Proteins / Q000235:genetics* / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D000097603:Dyrk Kinases
chemical_list: D001549:Benzamides; D000068877:Imatinib Mesylate; D051605:Kv Channel-Interacting Proteins; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D012097:Repressor Proteins; D000097603:Dyrk Kinases; C496749:KCNIP3 protein, human