AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment.
AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment.
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DOI：
10.1186/s12967-014-0216-z
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发表时间：
2014-07-31
影响因子：
7.4
通讯作者：
Ascierto PA
中科院分区：
文献类型：
--
作者：
Caputo E;Miceli R;Motti ML;Taté R;Fratangelo F;Botti G;Mozzillo N;Carriero MV;Cavalcanti E;Palmieri G;Ciliberto G;Pirozzi G;Ascierto PA
Aurora激酶A（AurkA）在黑色素瘤中过表达，并且已观察到其抑制可限制肿瘤生长，表明其在黑色素瘤治疗中的潜在作用。将具有B-RAF（V600 E）突变（A375 mel）的人黑素瘤细胞系暴露于B-RAF抑制剂（GSK 2118436）、MEK抑制剂（GSK 1120212）和AurkA抑制剂（MLN 8054）作为单一药剂或以各种组合（BRAF加AurkA抑制剂、MEK加AurkA抑制剂或BRAF加MEK加AurkA抑制剂的三重组合）。使用xCELLigence技术评估细胞增殖。通过Western印迹分析检测总蛋白提取物的p53和c-Myc蛋白表达。使用3D-人黑素瘤皮肤重建模型进一步评估药物抗肿瘤作用，其中将组织与含有对照、B-RAF加MEK抑制剂、MEK加AurkA抑制剂或三重组合的无血清培养基一起孵育。AurkA抑制剂加B-RAF抑制剂、AurkA抑制剂加MEK抑制剂或三联组合对A375（BRAFV 600 E）黑素瘤细胞的抗增殖作用显著大于单药。在3D人类皮肤模型中，三重组合在表皮/真皮接合处具有比对照或任一双重组合更大的抗肿瘤作用。然而，在真皮层中检测到S-100和Ki-67阳性染色的梭形细胞，表明存在存活和增殖的黑色素瘤细胞。这些发现为黑色素瘤研究提供了新的前景，包括B-RAF/AurkA联合抑制B-RAF突变的黑色素瘤和MEK/AurkA抑制剂联合治疗无B-RAF突变的患者。此外，我们第一次证明了B-RAF、MEK和AurkA抑制剂三联药物组合对黑色素瘤细胞生长的有效性增加，并可能被视为增强黑色素瘤临床反应的潜在治疗策略。然而，尽管这种三联药物组合在表皮/真皮交界处更有效，但真皮层中存在活的和增殖的黑色素瘤细胞可能导致耐药性和疾病复发。这些真皮细胞的分子特征可能是开发新的治疗策略的关键。
Aurora kinase A (AurkA) is over-expressed in melanoma and its inhibition has been observed to limit tumor growth, suggesting a potential role in melanoma treatment. A human melanoma cell line with the B-RAF (V600E) mutation (A375mel) was exposed to B-RAF inhibitor (GSK2118436), MEK inhibitor (GSK1120212) and AurkA inhibitor (MLN8054) as single agents or in various combinations (BRAF plus AurkA inhibitor, MEK plus AurkA inhibitor or triple combination BRAF plus MEK plus AurkA inhibitor). Cell proliferation was assessed using xCELLigence technology. Total protein extracts were examined for p53 and c-Myc protein expression by Western blot analysis. Drug anti-tumor effects were further assessed using a 3D-human melanoma skin reconstruction model, in which tissues were incubated with serum-free medium containing control, B-RAF plus MEK inhibitor, MEK plus AurkA inhibitor or the triple combination. AurkA inhibitor plus B-RAF inhibitor, AurkA inhibitor plus MEK inhibitor or triple combination had a markedly greater anti-proliferative effect on A375 (BRAFV600E) melanoma cells than single agents. In the 3D human skin model, the triple combination had a greater anti-tumor effect at the epidermal/dermal junction than control or either double combination. However, S-100 and Ki-67 positively stained spindle-shaped cells were detected in the dermal stratum, suggesting the presence of alive and proliferating melanoma cells. These findings provide new prospects for melanoma research, including combined B-RAF/AurkA inhibition for B-RAF mutated melanomas and MEK/AurkA inhibitor combination for patients without B-RAF mutations. Moreover, for the first time, we have shown that a B-RAF, MEK and AurkA inhibitor triple drug combination offers increased efficacy against melanoma cell growth and might be considered as a potential treatment strategy for enhancing clinical response in melanoma. However, although this triple drug combination was more effective at the epidermal/dermal junction, the suggested presence of alive and proliferating melanoma cells in the dermal stratum could result in drug resistance and disease recurrence. Molecular characterization of these dermal cells may be critical for the development of novel therapeutic strategies.
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影响因子：
3.7
作者：
Limame R;Wouters A;Pauwels B;Fransen E;Peeters M;Lardon F;De Wever O;Pauwels P
通讯作者：
Pauwels P
影响因子：
4.3
作者：
Liu, Dingxie;Liu, Xuan;Xing, Mingzhao
通讯作者：
Xing, Mingzhao
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
28.2
作者：
Shi H;Hugo W;Kong X;Hong A;Koya RC;Moriceau G;Chodon T;Guo R;Johnson DB;Dahlman KB;Kelley MC;Kefford RF;Chmielowski B;Glaspy JA;Sosman JA;van Baren N;Long GV;Ribas A;Lo RS
通讯作者：
Lo RS
影响因子：
11.1
作者：
Liu, Yan;Hawkins, Oriana E.;Su, Yingjun;Vilgelm, Anna E.;Sobolik, Tammy;Thu, Yee-Mon;Kantrow, Sara;Splittgerber, Ryan C.;Short, Sarah;Amiri, Katayoun I.;Ecsedy, Jeffery A.;Sosman, Jeffery A.;Kelley, Mark C.;Richmond, Ann
通讯作者：
Richmond, Ann