ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma

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• dc.contributor.author Smit, Marjon A.
• dc.contributor.author Maddalo, Gianluca
• dc.contributor.author Greig, Kylie
• dc.contributor.author Raaijmakers, Linsey M.
• dc.contributor.author Possik, Patricia A.
• dc.contributor.author van Breukelen, Bas
• dc.contributor.author Cappadona, Salvatore
• dc.contributor.author Heck, Albert J.R.
• dc.contributor.author Altelaar, AF Maarten
• dc.contributor.author Peeper, Daniel S.
• dc.date.accessioned 2025-01-14T08:13:24Z
• dc.date.available 2025-01-14T08:13:24Z
• dc.date.issued 2014
• dc.description.abstract Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibition sensitizes melanoma cells to BRAF inhibition. We found many proteins to be induced upon PLX4720 (BRAF inhibitor) treatment that are known to be involved in BRAF inhibitor resistance, including FOXD3 and ErbB3. Several proteins were down‐regulated, including Rnd3, a negative regulator of ROCK1 kinase. For our genomic approach, we performed two parallel shRNA screens using a kinome library to identify genes whose inhibition sensitizes to BRAF or ERK inhibitor treatment. By integrating our functional genomic and (phospho)proteomic data, we identified ROCK1 as a potential drug target for BRAF mutant melanoma. ROCK1 silencing increased melanoma cell elimination when combined with BRAF or ERK inhibitor treatment. Translating this to a preclinical setting, a ROCK inhibitor showed augmented melanoma cell death upon BRAF or ERK inhibition in vitro. These data merit exploration of ROCK1 as a target in combination with current BRAF mutant melanoma therapies.en
• dc.description.sponsorship We thank R. Kerkhoven and R. Beijersbergen for advice on the design and analysis of the shRNA screens, G. van Haaften and S. Huang for advice on the screening procedure, B, Gerritsen for statistical analysis of the screens, C.J. Vogel for STR profiling and N. Visser for excellent technical assistance. We thank E. M. Verdegaal and S. H. van der Burg for the 04.01, 93.03 and 00.08 melanoma cell lines. We thank Merck for financial support and for providing the ERK inhibitor. G.M. has been awarded an International postdoc grant from Vetenskapsrådet (VR), Sweden. K.G. was supported by an overseas training fellowship from the NHMRC Australia. A.F.M.A. and A.J.R.H. were supported by the Netherlands Proteomics Center, embedded in The Netherlands Genomics Initiative, and the PRIME‐XS Project, Grant Agreement 262067, funded by the European Union Seventh Framework Program. A.F.M.A. was supported by the Netherlands Organization for Scientific Research (NWO) with a VIDI grant (723.012.102). This work is part of the project Proteins At Work, financed by the Netherlands Organisation for Scientific Research (NWO) as part of the National Roadmap Large‐scale Research Facilities of the Netherlands (project number 184.032.201). D.S.P. and M.A.S. were supported by a Queen Wilhelmina award and a grant from KWF Kankerbestrijding.en
• dc.format.mimetype application/pdf
• dc.identifier.citation Smit MA, Maddalo G, Greig K, Raaijmakers LM, Possik PA, van Breukelen B, et al. ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma. Mol Syst Biol. 2014 Dec;10(12):772. DOI: 10.15252/msb.20145450
• dc.identifier.doi http://dx.doi.org/10.15252/msb.20145450
• dc.identifier.issn 1744-4292
• dc.identifier.uri http://hdl.handle.net/10230/69096
• dc.language.iso eng
• dc.publisher EMBO Press
• dc.relation.ispartof Molecular Systems Biology. 2014 Dec;10(12):772
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/262067
• dc.rights © 2014 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Kinome shRNA genomic screeningen
• dc.subject.keyword PLX4720en
• dc.subject.keyword Proteomicsen
• dc.subject.keyword ROCK1en
• dc.title ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion