A STATement on Vemurafenib-Resistant Melanoma

Hartsough, Edward J.; Aplin, Andrew E.

doi:10.1038/jid.2013.136

Cited by 9 publications

(6 citation statements)

References 8 publications

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“…However, continuous drug treatment was required to maintain the growth inhibitory response in both SA-4 sarcoma cells and the WM9 melanoma cell line, as cells regained growth following removal of vemurafenib at all tested concentrations. These findings indicate that there is a need for continuous treatment, should vemurafenib be used as a therapy against sarcoma, which is in agreement with experiences from treatment of other cancer types [ 37 , 38 ].…”

Section: Discussionsupporting

confidence: 83%

Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas

Gouravan

Meza‐Zepeda

Myklebost

et al. 2018

IJMS

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The BRAFV600E mutation, which in melanoma is targetable with vemurafenib, is also found in sarcomas and we here evaluate the therapeutic potential in sarcoma cell lines. Methods: Four sarcoma cell lines harboring the BRAFV600E mutation, representing liposarcomas (SA-4 and SW872), Ewing sarcoma (A673) and atypical synovial sarcoma (SW982), were treated with vemurafenib and the effects on cell growth, apoptosis, cell cycle progression and cell signaling were determined. Results: Vemurafenib induced a strong cytostatic effect in SA-4 cells, mainly due to cell cycle arrest, whereas only moderate levels of apoptosis were observed. However, a high dose was required compared to BRAFV600E mutated melanoma cells, and removal of vemurafenib demonstrated that the continuous presence of drug was required for sustained growth inhibition. A limited growth inhibition was observed in the other three cell lines. Protein analyses demonstrated reduced phosphorylation of ERK during treatment with vemurafenib in all the four sarcoma cell lines confirming that the MAPK pathway is active in these cell lines, and that the pathway can be inhibited by vemurafenib, but also that these cells can proliferate despite this. Conclusions: These findings indicate that vemurafenib alone would not be an efficient therapy against BRAFV600E mutated sarcomas. However, further investigations of combination with other drugs are warranted.

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Section: Discussionsupporting

confidence: 83%

Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas

Gouravan

Meza‐Zepeda

Myklebost

et al. 2018

IJMS

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“…In a manner independent on the MAPK pathway activation, up-regulation of the PDGFRβ receptor may promote the expression of the transcriptional activation factors STAT3 or PAX3, increasing cell survival and thus reducing the effectiveness of BRAF or MEK inhibition ( 83 , 103 ). As confirmation of this, inactivation of such genes may restore the block of malignant proliferation in vemurafenib-resistant melanoma cells ( 89 , 90 ).…”

Section: Acquired Resistancementioning

confidence: 99%

Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

et al. 2015

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Molecular mechanisms involved in pathogenesis of malignant melanoma have been widely studied and novel therapeutic treatments developed in recent past years. Molecular targets for therapy have mostly been recognized in the RAS–RAF–MEK–ERK and PI3K–AKT signaling pathways; small-molecule inhibitors were drawn to specifically target key kinases. Unfortunately, these targeted drugs may display intrinsic or acquired resistance and various evidences suggest that inhibition of a single effector of the signal transduction cascades involved in melanoma pathogenesis may be ineffective in blocking the tumor growth. In this sense, a wider comprehension of the multiple molecular alterations accounting for either response or resistance to treatments with targeted inhibitors may be helpful in assessing, which is the most effective combination of such therapies. In the present review, we summarize the known molecular mechanisms underlying either intrinsic and acquired drug resistance either alternative roads to melanoma pathogenesis, which may become targets for innovative anticancer approaches.

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“…Patients with late-stage BRAF mutant melanomas administered vemurafenib, the BRAF inhibitor mentioned above, show significant tumour regression and increased survival [ 142 , 143 ]. However, relatively rapid resistant is acquired with most patients relapsing with a lethal drug resistant phenotype [ 144 ]. Induction of ER-stress and the UPR in vemurafenib-resistance results in increased apoptosis [ 92 , 145 ].…”

Section: Upr and Chemotherapymentioning

confidence: 99%

Melanoma and the Unfolded Protein Response

Sykes

Mactier

Christopherson

2016

Cancers

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The UPR (unfolded protein response) has been identified as a key factor in the progression and metastasis of cancers, notably melanoma. Several mediators of the UPR are upregulated in cancers, e.g., high levels of GRP78 (glucose-regulator protein 78 kDa) correlate with progression and poor outcome in melanoma patients. The proliferative burden of cancer induces stress and activates several cellular stress responses. The UPR is a tightly orchestrated stress response that is activated upon the accumulation of unfolded proteins within the ER (endoplasmic reticulum). The UPR is designed to mediate two conflicting outcomtes, recovery and apoptosis. As a result, the UPR initiates a widespread signaling cascade to return the cell to homeostasis and failing to achieve cellular recovery, initiates UPR-induced apoptosis. There is evidence that ER stress and subsequently the UPR promote tumourigenesis and metastasis. The complete role of the UPR has yet to be defined. Understanding how the UPR allows for adaption to stress and thereby assists in cancer progression is important in defining an archetype of melanoma pathology. In addition, elucidation of the mechanisms of the UPR may lead to development of effective treatments of metastatic melanoma.

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A STATement on Vemurafenib-Resistant Melanoma

Cited by 9 publications

References 8 publications

Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas

Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas

Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets

Melanoma and the Unfolded Protein Response

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