MDM4 is a key therapeutic target in cutaneous melanoma.

Gembarska, Agnieszka; Luciani, Flavie; Fedele, Clare; Russell, Elisabeth A; Dewaele, Michael; Villar, Stéphanie; Zwolinska, Aleksandra; Haupt, Sue; de Lange, Job; Yip, Dana; Goydos, James; Haigh, Jody J; Haupt, Ygal; Larue, Lionel; Jochemsen, Aart; Shi, Hubing; Moriceau, Gatien; Lo, Roger S; Ghanem, Ghanem; Shackleton, Mark; Bernal, Federico; Marine, Jean-Christophe

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Updated in 8/12/2020 12:05:07 PM

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(Journal Article)

Nature medicine 18 (8): 1239-47 (2012)

MDM4 is a key therapeutic target in cutaneous melanoma.

Agnieszka Gembarska , Flavie Luciani , Clare Fedele , Elisabeth A Russell , Michael Dewaele , Stéphanie Villar , Aleksandra Zwolinska , Sue Haupt , Job de Lange , Dana Yip , James Goydos , Jody J Haigh , Ygal Haupt , Lionel Larue , Aart Jochemsen , Hubing Shi , Gatien Moriceau , Roger S Lo , Ghanem Ghanem , Mark Shackleton , Federico Bernal , Jean-Christophe Marine

ABSTRACT
The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.

DOI: 10.1038/nm.2863

ISSN: 1078-8956

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Position:	Professor
About me:	James Goydos, MD is widely recognized as an expert in melanoma research & surgical oncology. In his over 20 years of experience as a surgeon, he has conducted research that has translated into patient care, clinical trials, & cutting-edge treatment. His research and clinical trials have recorded growth arrest in melanoma cells, transforming the area of cancer genomics. Goydos has decades of experience as a Professor of Surgery and researcher at UMDNJ Robert Wood Johnson Medical School. He is an advocate for patient privacy and is recognized for leadership in patient care by the Cancer Institute of New Jersey and MRF. By 2020, his work in melanoma & innovative trials have led him to record numerous awards by Castle Connolly. He has helped individuals to better understand the mechanics of melanoma, the invasion of the dermis, and to see that it is not always a death sentence.
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