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Cancer Cell. 2015 Jan 12;27(1):85-96. doi: 10.1016/j.ccell.2014.11.006. Epub 2014 Dec 11.

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

Author information

1
Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
2
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
3
Targeted Therapy Team, The Institute of Cancer Research, London SW3 6JB, UK.
4
Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XR, UK.
5
Histology Unit, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
6
Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK.
7
University of Manchester, Christie NHS Foundation Trust, Manchester M20 4BX, UK.
8
Molecular Oncology Group, Cancer Research UK Manchester Institute, Manchester M20 4BX, UK. Electronic address: richard.marais@cruk.manchester.ac.uk.
9
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. Electronic address: caroline.springer@icr.ac.uk.

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.

Comment in

PMID:
25500121
PMCID:
PMC4297292
DOI:
10.1016/j.ccell.2014.11.006
[Indexed for MEDLINE]
Free PMC Article

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