I think that Peter found it, GILD's tipping point, when he pointed to the TBK1 activity of cyt387. Several recent indicators that it's an interesting target.
Not related to incy directly, but it's on my clipboard......
Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance
Novartis Institutes for Biomedical Research, Emeryville, California 94608, USA
Meghna Das Thakur,
Fernando Salangsang,
Nancy K. Pryer &
Darrin D. Stuart
Helen Diller Family Comprehensive Cancer Center & Department of Cellular & Molecular Pharmacology, University of California San Francisco, California 94143-0128, USA
Allison S. Landman &
Martin McMahon
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA
William R. Sellers
Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, 8091 Zürich, Switzerland
Mitchell P. Levesque &
Reinhard Dummer
Nature(2013)doi:10.1038/nature11814Received 19 May 2012 Accepted 29 November 2012 Published online 09 January 2013
Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with?=50% of tumours expressing the BRAF(V600E) oncoprotein1, 2. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance3, 4. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy5. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)MEKERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations. |
