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Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma
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.
- pan-RAF inhibitors also inhibit SRC family kinases
- The compounds do not induce paradoxical activation of ERK in RAS mutant cells
- The compounds are active in BRAF and NRAS mutant melanomas
- The compounds are active in PDXs resistant to BRAF or BRAF plus MEK inhibitors
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
∗ Corresponding author
∗∗ Corresponding author
This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/3.0/ ).
© 2015 Published by Elsevier B.V.