Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers.
Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers.
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DOI：
10.1126/scitranslmed.aal5148
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发表时间：
2017-05-31
影响因子：
17.1
通讯作者：
Mills GB
中科院分区：
文献类型：
--
作者：
Sun C;Fang Y;Yin J;Chen J;Ju Z;Zhang D;Chen X;Vellano CP;Jeong KJ;Ng PK;Eterovic AKB;Bhola NH;Lu Y;Westin SN;Grandis JR;Lin SY;Scott KL;Peng G;Brugge J;Mills GB
突变的 RAS 仍然顽抗靶向治疗的努力。在这里，我们证明，在 RAS 突变普遍存在的肿瘤谱系的多个 RAS 突变肿瘤模型中，聚 ADP 核糖聚合酶 (PARP) 抑制剂和 MEK 抑制剂联合治疗可在体外和体内引起意想不到的协同细胞毒性作用。 PARP 和 MEK 抑制剂组合的作用独立于 BRCA1/2 和 p53 突变状态，表明协同活性可能具有普遍性。 PARP 和 MEK 抑制剂组合在 RAS 突变肿瘤中的协同活性与以下因素相关：1) 诱导 BIM 介导的细胞凋亡，2) 同源重组 DNA 修复途径成分表达减少，3) 同源重组 DNA 损伤修复能力降低，4) DNA 损伤检查点活性降低，5) PARP 抑制剂诱导的 DNA 损伤增加，6) 血管分布减少，可通过诱导缺氧提高 PARP 抑制剂功效，以及7) PARP1蛋白升高，从而增加PARP抑制剂的捕获活性。从机制上讲，FOXO3a（RAS/MAPK 通路的靶标）的强制表达足以概括 MEK 抑制剂的功能后果，包括与 PARP 抑制剂的协同作用。因此，突变型 RAS 抑制 FOXO3a 的能力及其被 MEK 抑制剂逆转的能力至少部分解释了 RAS 突变型肿瘤中 PARP 和 MEK 抑制剂的协同作用。 PARP 和 MEK 抑制剂的合理组合值得对 RAS 突变肿瘤患者进行临床研究，而这些患者几乎没有有效的治疗选择。
Mutant RAS has remained recalcitrant to targeted therapy efforts. Here we demonstrate that combined treatment with poly ADP ribose polymerase (PARP) inhibitors and MEK inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with: 1) induction of BIM-mediated apoptosis, 2) decrease in expression of components of the homologous recombination DNA repair pathway, 3) decrease in homologous recombination DNA damage repair capacity, 4) decrease in DNA damage checkpoint activity, 5) increase in PARP inhibitor-induced DNA damage, 6) decrease in vascularity which could increase PARP inhibitor efficacy by inducing hypoxia, and 7) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
关于癌症基因组地图集的泛伴奏蛋白质组学观点。
影响因子：
16.6
作者：
Akbani, Rehan;Ng, Patrick Kwok Shing;Werner, Henrica M. J.;Shahmoradgoli, Maria;Zhang, Fan;Ju, Zhenlin;Liu, Wenbin;Yang, Ji-Yeon;Yoshihara, Kosuke;Li, Jun;Ling, Shiyun;Seviour, Elena G.;Ram, Prahlad T.;Minna, John D.;Diao, Lixia;Tong, Pan;Heymach, John V.;Hill, Steven M.;Dondelinger, Frank;Stadler, Nicolas;Byers, Lauren A.;Meric-Bernstam, Funda;Weinstein, John N.;Broom, Bradley M.;Verhaak, Roeland G. W.;Liang, Han;Mukherjee, Sach;Lu, Yiling;Mills, Gordon B.
通讯作者：
Mills, Gordon B.
影响因子：
9.9
作者：
Eijkelenboom, Astrid;Mokry, Michal;Burgering, Boudewijn M. T.
通讯作者：
Burgering, Boudewijn M. T.