Reactivation of p53 as therapeutic intervention for malignant melanoma

Purpose of review Targeted therapy of malignant melanoma recently experienced remarkable advances with gene mutation-based therapies with signaling pathway inhibitors (kinase inhibitors). The treatments prolong patients’ survival, but in general resistance is acquired and progression of disease occurs. Therefore, additional therapeutic targets are desperately needed. Recent findings The p53 tumor suppressor gene is rarely mutated in melanoma, but its functional attenuation is needed for tumor development. Recently, it was found that the essential p53 inhibitor Mdmx is very frequently overexpressed in melanoma. Mdmx displays both p53-dependent and p53-independent oncogenic effects needed for melanoma growth Summary Current melanoma therapy based upon kinase inhibitors shows robust initial clinical effect, but the duration of effect is limited. Inactivation of Mdmx in melanoma inhibits tumor growth also of kinase-inhibitor-resistant tumors. An observed synergistic effect of kinase-inhibition and Mdmx targeting can lead to better and more durable treatment of melanoma patients.

[1]  D. Neri,et al.  Pharmacotherapy of metastatic melanoma: emerging trends and opportunities for a cure. , 2013, Pharmacology & therapeutics.

[2]  T. Boggon,et al.  MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL , 2013, Pigment cell & melanoma research.

[3]  S. Kraft,et al.  Ras, Raf, and MAP Kinase in Melanoma , 2013, Advances in anatomic pathology.

[4]  K. Flaherty,et al.  BRAF in Melanoma: Current Strategies and Future Directions , 2013, Clinical Cancer Research.

[5]  S. Knapp,et al.  Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. , 2013, Cancer cell.

[6]  G. Pupo,et al.  Antiproliferative Effects of Continued Mitogen-Activated Protein Kinase Pathway Inhibition following Acquired Resistance to BRAF and/or MEK Inhibition in Melanoma , 2013, Molecular Cancer Therapeutics.

[7]  C. Miller,et al.  MERTK receptor tyrosine kinase is a therapeutic target in melanoma. , 2013, The Journal of clinical investigation.

[8]  D. Lane,et al.  Stapled peptides with improved potency and specificity that activate p53. , 2013, ACS chemical biology.

[9]  A. Costanzo,et al.  p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis , 2013, The Journal of experimental medicine.

[10]  D. Schadendorf,et al.  New developments in biomarkers for melanoma , 2013, Current opinion in oncology.

[11]  G. Wahl,et al.  MDM2, MDMX and p53 in oncogenesis and cancer therapy , 2013, Nature Reviews Cancer.

[12]  R. Murali,et al.  Pathology and genetics of uveal melanoma , 2013, Pathology.

[13]  V. Baladandayuthapani,et al.  Drug Resistance to Inhibitors of the Human Double Minute-2 E3 Ligase Is Mediated by Point Mutations of p53, but Can Be Overcome with the p53 Targeting Agent RITA , 2012, Molecular Cancer Therapeutics.

[14]  Hubing Shi,et al.  MDM4 is a key therapeutic target in cutaneous melanoma , 2012, Nature Medicine.

[15]  A. Sivachenko,et al.  A Landscape of Driver Mutations in Melanoma , 2012, Cell.

[16]  Thelma Thompson,et al.  Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization , 2012, Proceedings of the National Academy of Sciences.

[17]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[18]  R. Breitling,et al.  Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to other p53 activating agents , 2012, Cell Death and Disease.

[19]  M J Jager,et al.  Synergistic growth inhibition based on small-molecule p53 activation as treatment for intraocular melanoma , 2012, Oncogene.

[20]  A. Jochemsen,et al.  Chk2 mediates RITA-induced apoptosis , 2011, Cell Death and Differentiation.

[21]  R. Breitling,et al.  Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells , 2011, Cell Death and Disease.

[22]  C. Fletcher,et al.  p63 immunohistochemical staining is limited in soft tissue tumors. , 2011, American journal of clinical pathology.

[23]  M. Červinka,et al.  Camptothecin induces p53-dependent and -independent apoptogenic signaling in melanoma cells , 2011, Apoptosis.

[24]  A. Jochemsen,et al.  Abrogation of Wip1 expression by RITA-activated p53 potentiates apoptosis induction via activation of ATM and inhibition of HdmX , 2011, Cell Death and Differentiation.

[25]  Gerry Melino,et al.  p73 in Cancer. , 2011, Genes & cancer.

[26]  Sarah G. Bailey,et al.  Family friction as ΔNp73 antagonises p73 and p53. , 2011, The international journal of biochemistry & cell biology.

[27]  Ming Chen,et al.  PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo , 2011, Cell cycle.

[28]  Tina N. Davis,et al.  A stapled p53 helix overcomes HDMX-mediated suppression of p53. , 2010, Cancer cell.

[29]  V. Grinkevich,et al.  Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA. , 2010, Cell Cycle.

[30]  P. Hainaut,et al.  Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis , 2010, Oncogene.

[31]  Damlanur Sakiz,et al.  The expression of p63 and p53 in keratoacanthoma and intraepidermal and invasive neoplasms of the skin. , 2009, Pathology, research and practice.

[32]  B. Pützer,et al.  Antisense gapmers selectively suppress individual oncogenic p73 splice isoforms and inhibit tumor growth in vivo , 2009, Molecular Cancer.

[33]  Jan Bergman,et al.  PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. , 2009, Cancer cell.

[34]  Sabine Siesling,et al.  Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. , 2008, European journal of cancer.

[35]  E. Feinstein,et al.  Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway , 2008, Proceedings of the National Academy of Sciences.

[36]  A. Schätzlein,et al.  A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo. , 2007, The Journal of clinical investigation.

[37]  S. Korsmeyer,et al.  Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. , 2007, Journal of the American Chemical Society.

[38]  Xin Lu,et al.  ASPP: a new family of oncogenes and tumour suppressor genes , 2007, British Journal of Cancer.

[39]  L. Chin,et al.  Malignant melanoma: genetics and therapeutics in the genomic era. , 2006, Genes & development.

[40]  L. Chin,et al.  Amplification of CDK4 and MDM2 in malignant melanoma , 2006, Genes, chromosomes & cancer.

[41]  M. Protopopova,et al.  Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors , 2004, Nature Medicine.

[42]  J. Levine,et al.  Surfing the p53 network , 2000, Nature.

[43]  A. Jochemsen,et al.  High levels of Hdmx promote cell growth in a subset of uveal melanomas. , 2012, American journal of cancer research.

[44]  Michael A Davies,et al.  The role of the PI3K-AKT pathway in melanoma. , 2012, Cancer journal.

[45]  Magali Olivier,et al.  TP53 mutations in human cancers: origins, consequences, and clinical use. , 2010, Cold Spring Harbor perspectives in biology.

[46]  Josep Malvehy,et al.  Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. , 2010, European journal of cancer.

[47]  M. Hollstein,et al.  p53 and human cancer: the first ten thousand mutations. , 2000, Advances in cancer research.