MDM4 is a key therapeutic target in cutaneous melanoma. (Nature Medicine 2012, 18(8):1239-1247)

報告日期: 2013/05/03
報告時間: 16:00/16:50
報告學生: 曾雅萍
講評老師: 洪澤民
附件下載: 下載[1311-1365562820-1.pdf] 

MDM4 is a key therapeutic target in cutaneous melanoma

Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S, Zwolinska A, Haupt S, de Lange J, Yip D, Goydos J, Haigh JJ, Haupt Y, Larue L, Jochemsen A, Shi H, Moriceau G, Lo RS, Ghanem G, Shackleton M, Bernal F, Marine JC.

Nature Medicine 18, 1239–1247 (2012)

Presenter: Ya-Ping Tseng                       Date: 05/03/2013 16:10-17:00

Commentator: Tse-Ming Hong, Ph.D              Place: Room 602

Therapeutic resistance and proclivity for metastasis are characteristics of cutaneous melanoma. Mutations in the p53 often occur in human cancer, but melanoma TP53 mutations are rare1. Previously studies indicated that MDM4 levels (p53 binding protein homolog)can determine the sensitivity of tumor cells for anti-cancer therapy2. p53-MDM4 interaction plays an important role in melanoma formation. In this article, MDM4 overexpression was observed in most melanomas except for human melanocyte. High MDM4 overexpression promoted tumorigenesis, melanoma, especially in transgenic mice. Furthermore, MDM4 could deactivate TP53, leading to anti-apoptosis in tumor cells, and the inhibition of MDM4-p53 interaction restoredp53 function in melanoma cells by SAH-p53-8 (a potent MDM4 binder). In human melanoma cell lines with high MDM4 and low MDM2 levels, SAH-p53-8 indeed significantly increased apoptosis capability, but nutlin-3 had only a marginal cytotoxic effect. The combination of both compounds couldmodest increase sensitivity in cytotoxicity.Next, remarkable inhibition of cells growth via combination with SAH-p53-8 and DNA-damaging agents was observed, possibly through apoptosis. Notably, targeting the MDM4-p53 interaction could affect the growth of BRAF inhibitor-resistant melanoma cell lines. Then, co-treatment of BRAF inhibitor (PLX4032) and SAH-p53-8 with cells potently enhanced the cytotoxicity. Therefore, inhibition of MDM4-p53 interaction with drug combination therapy in human melanoma may be a good strategy for preclinical development.

References:

1.     Albino A.P., Mutation and expression of the p53 gene in human malignant melanoma. Melanoma Res. 1994 Feb;4(1):35-45.

2.     Wade M. et al., MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013 Feb;13(2):83-96.