Understanding Melanoma Signaling Networks as the Basis for Molecular Targeted Therapy

Smalley, Keiran S.M.

doi:10.1038/jid.2009.177

Cited by 120 publications

(119 citation statements)

References 97 publications

(75 reference statements)

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“…We showed that LAG-3 can activate MAPK/Erk and PI3K/Akt survival pathways, both being highly implicated in melanoma resistance to apoptosis and progression (41). We have previously shown that anti-HLA-DR L243 activates MAPK/Erk but not PI3K/Akt pathway in melanoma cells (10).…”

Section: Discussionmentioning

confidence: 99%

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

Hémon

Jean-Louis

Ramgolam

et al. 2011

The Journal of Immunology

200

143

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Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3–transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3–induced protection from apoptosis. Altogether, our data suggest that the LAG-3–MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3–MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.

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Section: Discussionmentioning

confidence: 99%

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

Hémon

Jean-Louis

Ramgolam

et al. 2011

The Journal of Immunology

200

143

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“…3C). (23,24). We, therefore, examined if ERK activation in the PLX-selected cells is due to extracellular stimulation afforded by FCS in culture medium by reducing its concentration from 5% to 0.5%.…”

Section: Activation Of Erk Contributes To Survival Of Plxselected Melmentioning

confidence: 99%

MEK-Independent Survival of B-RAFV600E Melanoma Cells Selected for Resistance to Apoptosis Induced by the RAF Inhibitor PLX4720

Jiang

Lai

Thorne

et al. 2011

Clinical Cancer Research

104

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Purpose: To examine mechanisms that determine long-term responses of B-RAF V600E melanoma cells to B-RAF inhibitors. Experimental Design: B-RAF V600E melanoma cells were exposed to the B-RAF inhibitor PLX4720 for prolonged periods to select for cells resistant to apoptosis induced by the inhibitor. The resultant cells were analyzed for activation of extracellular signal regulated kinase (ERK), MAP/ERK kinase (MEK), and Akt, and related signals. Their roles in survival of the cells were also examined.Results: B-RAF V600E melanoma cells selected for resistant to PLX4720-induced apoptosis retained the V600E mutation in B-RAF, and proliferated steadily in the presence of the inhibitor, albeit with slow growth rate. These cells displayed high levels of ERK activation, that is, at least in part, independent of the conventional RAF/MEK/ERK pathway, as MEK activation was low and inhibition of MEK did not significantly block activation of ERK. In contrast, extracellular signals appeared involved. This was associated with elevated activation of the phosphoinositide 3-kinase (PI3k)/Akt pathway and could be inhibited by serum starvation and inhibition of PI3k/Akt. Inhibition of MEK did not impact on survival of these cells, whereas serum starvation, inhibition of PI3K/Akt, and inhibition of ERK1/2 reduced their viability.Conclusions: These results indicate that sensitivity to induction of apoptosis may be a major determinant of long-term responses of B-RAF V600E melanomas to specific inhibitors and suggest that rebound melanoma growth after initial treatment with the inhibitors may not be responsive to MEK inhibitors, but may be susceptible to inhibition of the PI3k/Akt pathway.

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“…Mutant BRAF melanoma progresyonunu Ras/Raf/MEK/ ERK MAPK (mitogen activated protein kinase) yola¤ını etkileyerek melanomu ilerletmekte ve hücre ço¤almasını artırarak invazyon ve sa¤kalımı etkileyerek, onkojenik fenotip melanomaya katkı-da bulunmaktadır. [2,3] ‹lginç olarak, BRAF mutasyonu melanoma geliiminin erken evresine katkı-da bulunurken, %80'den fazla benign nevüslerde BRAF V600E mutasyonu da gözlenmektedir. [4] Bu paradoks (melanositik nevüslerde olan BRAF V600E mutantının melanomaya ilerlememesi) 2006'da tümör supresör p16 ve beta galaktozidaz belirtecinin yüksek olmasına ba¤lanmıtır.…”

Section: Tartimaunclassified

A case of eruptive melanocytic naevi after long-term azathioprine treatment

Eken¹

2016

FNG & Bilim Tıp Dergisi

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Understanding Melanoma Signaling Networks as the Basis for Molecular Targeted Therapy

Cited by 120 publications

References 97 publications

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

MEK-Independent Survival of B-RAFV600E Melanoma Cells Selected for Resistance to Apoptosis Induced by the RAF Inhibitor PLX4720

A case of eruptive melanocytic naevi after long-term azathioprine treatment

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