Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases

Smalley, Keiran S.M., Haass, Nikolas K., Brafford, Patricia A., Lioni, Mercedes, Flaherty, Keith T. and Herlyn, Meenhard (2006) Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Molecular Cancer Therapeutics, 5 5: 1136-1144. doi:10.1158/1535-7163.MCT-06-0084


Author Smalley, Keiran S.M.
Haass, Nikolas K.
Brafford, Patricia A.
Lioni, Mercedes
Flaherty, Keith T.
Herlyn, Meenhard
Title Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases
Journal name Molecular Cancer Therapeutics   Check publisher's open access policy
ISSN 1535-7163
1538-8514
Publication date 2006-05-01
Sub-type Article (original research)
DOI 10.1158/1535-7163.MCT-06-0084
Open Access Status Not yet assessed
Volume 5
Issue 5
Start page 1136
End page 1144
Total pages 9
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Abstract Although >66% of melanomas harbor activating mutations in BRAF and exhibit constitutive activity in the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase signaling pathway, it is unclear how effective MEK inhibition will be as a sole therapeutic strategy for melanoma. We investigated the anticancer activity of MEK inhibition in a panel of cell lines derived from radial growth phase (WM35) and vertical growth phase (WM793) of primary melanomas and metastatic melanomas (1205Lu, 451Lu, WM164, and C8161) in a three-dimensional spheroid model and found that the metastatic lines were completely resistant to MEK inhibition (UO126 and PD98059) but the earlier stage cell lines were not. Similarly, these same metastatic melanoma lines were also resistant to inhibitors of the phosphatidylinositol 3-kinase/Akt pathway (LY294002 and wortmannin). Under adherent culture conditions, the MEK inhibitors blocked growth through the induction of cell cycle arrest and up-regulation of p27, but this was readily reversible following inhibitor washout. However, when the phosphatidylinositol 3-kinase and MEK inhibitors were combined, the growth and invasion of the metastatic melanoma three-dimensional spheroids were blocked. Taken together, these results suggest that the most aggressive melanomas are resistant to strategies targeting one signaling pathway and that multiple signaling pathways may need to be targeted for maximal therapeutic efficacy. It is further suggested that BRAF mutational status is not predictive of response to MEK inhibition under three-dimensional culture conditions. Copyright
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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Created: Sat, 31 May 2014, 04:13:51 EST by Nikolas Haass on behalf of Learning and Research Services (UQ Library)