The BH3 mimetic ABT-263 synergizes with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance.
The BH3 mimetic ABT-263 synergizes with the MEK1/2 inhibitor selumetinib/AZD6244 to promote BIM-dependent tumour cell death and inhibit acquired resistance.
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BH3 模拟物 ABT-263 与 MEK1/2 抑制剂 selumetinib/AZD6244 协同作用，促进 BIM 依赖性肿瘤细胞死亡并抑制获得性耐药。
DOI：
10.1042/bj20121212
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Sale MJ
中科院分区：
文献类型：
--
作者：
Sale MJ
肿瘤细胞通常对MEK 1/2 [丝裂原活化蛋白激酶/ERK（细胞外信号调节激酶）激酶1/2]抑制剂selumetinib表现出G1细胞周期停滞，但不会死亡，因此它们获得耐药性。在本研究中，我们检查了司美替尼与BH 3 [BCL 2（B细胞淋巴瘤2）同源结构域3]模拟BCL 2抑制剂ABT-263组合的效果。尽管单独使用这两种药物几乎不引起肿瘤细胞死亡，但这两种药物联合使用可引起大量半胱天冬酶依赖性细胞死亡，并抑制BRAFV 600 E或RAS突变的结直肠癌和黑色素瘤细胞系的长期克隆存活。这种细胞死亡绝对需要BAX（BCL 2相关的X蛋白），并且在BRAFV 600 E阳性COLO 205细胞系中通过RNAi（RNA干扰）介导的BIM（BCL 2相互作用的细胞死亡介质）敲低来抑制。当结肠直肠癌细胞系用司美替尼加ABT-263处理时，我们观察到对司美替尼产生获得性耐药性的细胞的发生率显著降低。当我们将ABT-263与BRAFV 600 E选择性抑制剂PLX 4720组合时，观察到类似的结果，但仅在表达BRAFV 600 E的细胞中。最后，通过BRAFV 600 E扩增产生对司美替尼获得性耐药的癌细胞对ABT-263仍然敏感，而司美替尼耐药的HCT 116细胞（KRASG 13 D扩增）对ABT-263交叉耐药。因此，BCL 2抑制剂和ERK 1/2途径抑制剂的组合在ERK 1/2成瘾的肿瘤细胞中是合成致死的，延迟获得性耐药性的发生，并且在某些情况下克服对司美替尼的获得性耐药性。
Tumour cells typically exhibit a G1cell cycle arrest in response to the MEK1/2 [mitogen-activated protein kinase/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitor selumetinib, but do not die, and thus they acquire resistance. In the present study we examined the effect of combining selumetinib with the BH3 [BCL2 (B-cell lymphoma 2) homology domain 3]-mimetic BCL2 inhibitor ABT-263. Although either drug alone caused little tumour cell death, the two agents combined to cause substantial caspase-dependent cell death and inhibit long-term clonogenic survival of colorectal cancer and melanoma cell lines with BRAFV600Eor RAS mutations. This cell death absolutely required BAX (BCL2-associated X protein) and was inhibited by RNAi (RNA interference)-mediated knockdown of BIM (BCL2-interacting mediator of cell death) in the BRAFV600E-positive COLO205 cell line. When colorectal cancer cell lines were treated with selumetinib plus ABT-263 we observed a striking reduction in the incidence of cells emerging with acquired resistance to selumetinib. Similar results were observed when we combined ABT-263 with the BRAFV600E-selective inhibitor PLX4720, but only in cells expressing BRAFV600E. Finally, cancer cells in which acquired resistance to selumetinib arises through BRAFV600Eamplification remained sensitive to ABT-263, whereas selumetinib-resistant HCT116 cells (KRASG13Damplification) were cross-resistant to ABT-263. Thus the combination of a BCL2 inhibitor and an ERK1/2 pathway inhibitor is synthetic lethal in ERK1/2-addicted tumour cells, delays the onset of acquired resistance and in some cases overcomes acquired resistance to selumetinib.
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影响因子：
45.3
作者：
Roberts, Andrew W.;Seymour, John F.;Humerickhouse, Rod
通讯作者：
Humerickhouse, Rod
影响因子：
11.2
作者：
Zhang W;Konopleva M;Burks JK;Dywer KC;Schober WD;Yang JY;McQueen TJ;Hung MC;Andreeff M
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Andreeff M
影响因子：
11.2
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Montagut, Clara;Sharma, Sreenath V.;Settleman, Jeffrey
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Settleman, Jeffrey
影响因子：
16
作者：
Kuwana, T;Bouchier-Hayes, L;Newmeyer, DD
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Newmeyer, DD
影响因子：
50.3
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Villanueva J;Vultur A;Lee JT;Somasundaram R;Fukunaga-Kalabis M;Cipolla AK;Wubbenhorst B;Xu X;Gimotty PA;Kee D;Santiago-Walker AE;Letrero R;D'Andrea K;Pushparajan A;Hayden JE;Brown KD;Laquerre S;McArthur GA;Sosman JA;Nathanson KL;Herlyn M
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Herlyn M