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Please use this identifier to cite or link to this item: http://hdl.handle.net/1959.14/294544
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- Title
- Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition
- Related
- Journal of investigative dermatology, Vol. 132, No. 7, (2012), p.1850-1859
- DOI
- 10.1038/jid.2012.63
- Publisher
- Nature Publishing Group
- Date
- 2012
- Author/Creator
- Gowrishankar, Kavitha
- Author/Creator
- Snoyman, Stephanie
- Author/Creator
- Pupo, Gulietta M
- Author/Creator
- Becker, Therese M
- Author/Creator
- Kefford, Richard F
- Author/Creator
- Rizos, Helen
- Description
- Aberrant activation of the BRAF kinase occurs in ~60% of melanomas, and although BRAF inhibitors have shown significant early clinical success, acquired resistance occurs in most patients. Resistance to chronic BRAF inhibition often involves reactivation of mitogen-activated protein kinase (MAPK) signaling, and the combined targeting of BRAF and its downstream target MAPK/ERK kinase (MEK) may delay or overcome resistance. To investigate the efficacy of combination BRAF and MEK inhibition, we generated melanoma cell clones resistant to the BRAF inhibitor GSK2118436. These BRAF inhibitor-resistant sublines acquired resistance through several distinct mechanisms, including the acquisition of activating N-RAS mutations and increased accumulation of COT1. These alterations uniformly promoted MAPK reactivation and most conferred resistance to MEK inhibition and to the concurrent inhibition of BRAF and MEK. These data indicate that melanoma tumors are likely to develop heterogeneous mechanisms of resistance, many of which will confer resistance to multiple MAPK inhibitory therapies. Corrigendum exists for this article and can be found in the Journal of investigative dermatology, 133(10), p. 2493, doi:10.1038/jid.2013.125
- Description
- 10 page(s)
- Subject Keyword
- 111200 Oncology and Carcinogenesis
- Resource Type
- journal article
- Organisation
- Macquarie University. Australian School of Advanced Medicine
- Identifier
- http://hdl.handle.net/1959.14/294544
- Identifier
- mq:31774
- Identifier
- ISSN:0022-202X
- Identifier
- mq-rm-2013003302
- Identifier
- mq_res-ext-2-s2.0-84862305656
- Language
- eng
- Reviewed
Macquarie University ResearchOnline
