Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

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. NathansonMeenhard Herlyn*

*Corresponding author for this work

Research output: Contribution to journalArticle

906 Scopus citations

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 BRAFV600E 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.

Original languageEnglish (US)
Pages (from-to)683-695
Number of pages13
JournalCancer Cell
Volume18
Issue number6
DOIs
StatePublished - Dec 14 2010

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Villanueva, J., Vultur, A., Lee, J. T., Somasundaram, R., Fukunaga-Kalabis, M., Cipolla, A. K., Wubbenhorst, B., Xu, X., Gimotty, P. A., Kee, D., Santiago-Walker, A. E., Letrero, R., D'Andrea, K., Pushparajan, A., Hayden, J. E., Brown, K. D., Laquerre, S., McArthur, G. A., Sosman, J. A., ... Herlyn, M. (2010). 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, 18(6), 683-695. https://doi.org/10.1016/j.ccr.2010.11.023