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

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.

• Authors: Jessie Villanueva, Adina Vultur, John T Lee, Rajasekharan Somasundaram, Mizuho Fukunaga-Kalabis, Angela K Cipolla, Bradley Wubbenhorst, Xiaowei Xu, Phyllis A Gimotty, Damien Kee, Ademi E Santiago-Walker, Richard Letrero, Kurt D'Andrea, Anitha Pushparajan, James E Hayden, Kimberly Dahlman Brown, Sylvie Laquerre, Grant A McArthur, Jeffrey A Sosman, Katherine L Nathanson, Meenhard Herlyn
• Journal: Cancer cell (Cancer Cell) Vol. 18 Issue 6 Pg. 683-95 (Dec 14 2010) ISSN: 1878-3686 [Electronic] United States
• PMID: 21156289 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• 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)