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PMID: 21156289 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K.

Cancer cell ·Vol. 18 ·No. 6 ·2010-12-14 ·Pages 683-95

Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D'Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M

Abstract

BRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAF(V)⁶⁰⁰(E) melanoma cells with the BRAF inhibitor SB-590885; these cells are cross-resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors.

MeSH Terms
Cell Line, Tumor Drug Resistance, Neoplasm Humans MAP Kinase Signaling System Melanoma/drug therapy,pathology Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors Phosphatidylinositol 3-Kinases/physiology Phosphoinositide-3 Kinase Inhibitors Phosphorylation Proto-Oncogene Proteins B-raf/antagonists & inhibitors Proto-Oncogene Proteins c-akt/metabolism Receptor, IGF Type 1/antagonists & inhibitors,physiology raf Kinases/physiology
Chemicals
Phosphoinositide-3 Kinase Inhibitors Receptor, IGF Type 1 Proto-Oncogene Proteins B-raf Proto-Oncogene Proteins c-akt raf Kinases Mitogen-Activated Protein Kinase Kinases
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Villanueva Jessie
The Wistar Institute, Philadelphia, PA 19104, USA.
Vultur Adina
Lee John T
Somasundaram Rajasekharan
Fukunaga-Kalabis Mizuho
Cipolla Angela K
Wubbenhorst Bradley
Xu Xiaowei
Gimotty Phyllis A
Kee Damien
Santiago-Walker Ademi E
Letrero Richard
D'Andrea Kurt
Pushparajan Anitha
Hayden James E
Brown Kimberly Dahlman
Laquerre Sylvie
McArthur Grant A
Sosman Jeffrey A
Nathanson Katherine L
Herlyn Meenhard
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2010.11.023
Published
2010-12-14
Pages
683-95
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3026446
Subset
IM
Grants
NCI NIH HHS · P01 CA114046-01A2 · United States
NCI NIH HHS · P30 CA010815 · United States
NCI NIH HHS · P01 CA114046 · United States
NCI NIH HHS · K24 CA097588 · United States
NCI NIH HHS · P50 CA093372-01 · United States
NCI NIH HHS · R01 CA117881 · United States
NCI NIH HHS · P01 CA025874 · United States
NCI NIH HHS · P50 CA093372 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2010.11.023 PMC Full Text View journal details
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