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A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status


Zipser, M C; Eichhoff, O M; Widmer, D S; Schlegel, N C; Schoenewolf, N L; Stuart, D; Liu, W; Gardner, H; Smith, P D; Nuciforo, P; Dummer, R; Hoek, K S (2011). A proliferative melanoma cell phenotype is responsive to RAF/MEK inhibition independent of BRAF mutation status. Pigment Cell & Melanoma Research, 24(2):326-333.

Abstract

Oncogenic mutations within the MAPK pathway are frequent in melanoma, and targeting of MAPK signaling has yielded spectacular responses in a significant number of patients that last for several months before relapsing. We investigated the effects of two different inhibitors of MAPK signaling in proliferative and invasive melanoma cell cultures with various mutations in the MAPK pathway. Proliferative melanoma cells were more susceptible to pathway inhibition than invasive phenotype cells, irrespective of BRAF mutation status, while invasive phenotype cell response was dependent on BRAF mutation status. Critically, MAPK pathway inhibition of proliferative phenotype cells resulted in acquisition of invasive phenotype characteristics. These results show that melanoma cell phenotype is an important factor in MAPK pathway inhibition response. This suggests that while current therapeutic strategies target proliferative melanoma cells, future approaches should also account for the invasive phenotype population.

Oncogenic mutations within the MAPK pathway are frequent in melanoma, and targeting of MAPK signaling has yielded spectacular responses in a significant number of patients that last for several months before relapsing. We investigated the effects of two different inhibitors of MAPK signaling in proliferative and invasive melanoma cell cultures with various mutations in the MAPK pathway. Proliferative melanoma cells were more susceptible to pathway inhibition than invasive phenotype cells, irrespective of BRAF mutation status, while invasive phenotype cell response was dependent on BRAF mutation status. Critically, MAPK pathway inhibition of proliferative phenotype cells resulted in acquisition of invasive phenotype characteristics. These results show that melanoma cell phenotype is an important factor in MAPK pathway inhibition response. This suggests that while current therapeutic strategies target proliferative melanoma cells, future approaches should also account for the invasive phenotype population.

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23 citations in Web of Science®
25 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:27 Jul 2011 13:08
Last Modified:05 Apr 2016 14:57
Publisher:Wiley-Blackwell
ISSN:1755-1471
Publisher DOI:10.1111/j.1755-148X.2010.00823.x
PubMed ID:21176117
Permanent URL: http://doi.org/10.5167/uzh-48819

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