RGD Reference Report - Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy. - Rat Genome Database

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Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy.

Authors: Yang, J  Zaja-Milatovic, S  Thu, YM  Lee, F  Smykla, R  Richmond, A 
Citation: Yang J, etal., Mol Cancer Ther. 2009 Mar;8(3):636-47. doi: 10.1158/1535-7163.MCT-08-0749. Epub 2009 Mar 10.
RGD ID: 7495758
Pubmed: PMID:19276165   (View Abstract at PubMed)
PMCID: PMC3140401   (View Article at PubMed Central)
DOI: DOI:10.1158/1535-7163.MCT-08-0749   (Journal Full-text)

The BRAFV600E mutation is common in human melanoma. This mutation enhances IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKbeta in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma. Xenografts of Hs294T human metastatic melanoma cells exhibiting the BRAFV600E mutation were treated with inhibitors of IKKbeta (BMS-345541), B-Raf (BAY 54-9085), and/or temozolomide. Drug response was mechanistically analyzed in vitro and in vivo. In this study, we determined that the antitumor activity of all three drugs depends on inhibition of NF-kappaB. BMS-345541 inhibits IKKbeta-mediated phosphorylation of IkappaBalpha and thus blocks the nuclear localization of NF-kappaB, whereas BAY 54-9085 inhibits activation of NF-kappaB through a mechanism that does not involve stabilization of IkappaBalpha. Moreover, BMS-345541, but not BAY 54-9085, activates the death pathways of p53 and c-Jun-NH2-kinase, contributing to the killing of melanoma cells. Temozolomide inhibits both NF-kappaB and extracellular signal-regulated kinase activity, conferring effective in vivo antitumor activity. Thus, temozolomide, but not BAY 54-9085, has a synergistic in vivo antitumor effect with BMS-345541. We conclude that the efficacy of antimelanoma therapy depends on inhibition of expression of antiapoptotic genes transcriptionally regulated by NF-kappaB. In contrast, drug targeting of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway alone in melanoma cells is ineffective for melanoma therapy in cases where NF-kappaB is not also targeted.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Melanoma  IMP 7495758 RGD 
Experimental Melanoma  ISOIKBKB (Homo sapiens)7495758; 7495758 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ikbkb  (inhibitor of nuclear factor kappa B kinase subunit beta)

Genes (Mus musculus)
Ikbkb  (inhibitor of kappaB kinase beta)

Genes (Homo sapiens)
IKBKB  (inhibitor of nuclear factor kappa B kinase subunit beta)


Additional Information