Molecular and Cellular Pathobiology The DREAM Complex Mediates GIST Cell Quiescence and Is a Novel Therapeutic Target to Enhance Imatinib-Induced Apoptosis
Molecular and Cellular Pathobiology The DREAM Complex Mediates GIST Cell Quiescence and Is a Novel Therapeutic Target to Enhance Imatinib-Induced Apoptosis
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2013
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通讯作者：
S. Boichuk;Joshua A. Parry;Kathleen R. Makielski;Larisa Litovchick;Julianne L. Baron;James P. Zewe;A. Wozniak;Keith R. Mehalek;N. Korzeniewski;D. Seneviratne;M. Debiec-Rychter;J. Decaprio;A. Duensing
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作者：
S. Boichuk;Joshua A. Parry;Kathleen R. Makielski;Larisa Litovchick;Julianne L. Baron;James P. Zewe;A. Wozniak;Keith R. Mehalek;N. Korzeniewski;D. Seneviratne;M. Debiec-Rychter;J. Decaprio;A. Duensing
胃肠道间质瘤(GIST)可以用甲磺酸伊马替尼(Gleevec)成功治疗；然而，完全缓解是罕见的，患者经常在残留肿瘤肿块的情况下实现疾病稳定。停止治疗会导致肿瘤进展的临床观察表明，残留的肿瘤细胞实际上处于静止状态，因此能够重新进入细胞分裂周期。与这一观点一致，我们先前已经证明，伊马替尼通过APC-Skp2-p27信号轴在体外诱导GIST细胞静止。在这里，我们提供了伊马替尼在体内诱导GIST细胞静止的证据，并且这一过程还涉及梦复合体，这是一种多亚单位复合体，最近被发现是静止的额外关键调节因子。重要的是，通过耗尽DREAM调节激酶DYRK1A或其靶点LIN52来抑制DREAM复合体的形成，发现可以增强伊马替尼诱导的细胞死亡。我们的结果表明，伊马替尼诱导了部分GIST细胞的凋亡，同时，一部分细胞经历了涉及梦境复合体的静止。抑制这一过程可增强伊马替尼诱导的细胞凋亡，这为未来的治疗干预打开了机会，使其针对梦想复合体，获得更有效的伊马替尼反应。癌症资源；73(16)；5120-9。2013 AACR。
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–SKP2–p27 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. Cancer Res; 73(16); 5120–9. 2013 AACR.