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Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma.

Girotti, Maria Romina
; 
Lopes, F
; 
Preece, N
; 
Niculescu-Duvaz, D
; 
Zambon, A
; 
Davies, L
; 
Whittaker, S
; 
Saturno, G
; 
Viros, A
; 
Pedersen, M
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Abstract
BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance.
Authors
Girotti, Maria Romina
Lopes, F
Preece, N
Niculescu-Duvaz, D
Zambon, A
Davies, L
Whittaker, S
Saturno, G
Viros, A
Pedersen, M
Suijkerbuijk, B
Menard, D
McLeary, R
Johnson, L
Fish, L
Ejiama, S
Sanchez-Laorden, B
Hohloch, J
Carragher, N
Macleod, K
Ashton, Garry
Marusiak, Anna A
Fusi, Alberto
Brognard, John
Frame, M
Lorigan, Paul C
Marais, Richard
Springer, C
Affiliation
Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX,
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2014-12-10
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All Christie Publications
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Article
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Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. 2014: Cancer Cell
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http://hdl.handle.net/10541/337935
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