PLX4032, a selective BRAF V600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF WT melanoma cells

Abstract

BRAF(V600E/K) is a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032. Our studies with melanoma tumor cells that are BRAF(V600E/K) and BRAF(WT) showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAF(V600E/K), it activated the pathway in the resistant BRAF(WT) cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK1/2 triggered downstream effectors in BRAF(WT) melanoma cells and induced changes in the expression of a wide-spectrum of genes associated with cell cycle control. Furthermore, PLX4032 increased the rate of proliferation of growth factor-dependent NRAS Q61L mutant primary melanoma cells, reduced cell adherence and increased mobility of cells from advanced lesions. The results suggest that the drug can confer an advantage to BRAF(WT) primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses.

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References 29

1. 1.

   Baccarini M. Second nature: biological functions of the Raf-1 “kinase”. FEBS Lett. 2005;579:3271-3277.

   Not in our library10.1016/j.febslet.2005.03.024

2. 2.

   Bild AH, Yao G, Chang JT, et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature. 2006;439:353-357.

   Not in our library10.1038/nature04296

3. 3.

   Böhm M, Moellmann G, Cheng E, Alvarez-Franco M, Wagner S, Sassone-Corsi P, Halaban R. Identification of p90RSK as the probable CREB-Ser133 kinase in human melanocytes. Cell Growth Differ. 1995;6:291-302.

   Not in our library

4. 4.

   Craig EA, Stevens MV, Vaillancourt RR, Camenisch TD. MAP3Ks as central regulators of cell fate during development. Dev. Dyn. 2008;237:3102-3114.

   Not in our library10.1002/dvdy.21750

5. 5.

   Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 2006;24:4340-4346.

   Not in our library10.1200/jco.2006.06.2984

6. 6.

   Dent P, Reardon DB, Morrison DK, Sturgill TW. Regulation of Raf-1 and Raf-1 mutants by Ras-dependent and Ras-independent mechanisms in vitro. Mol. Cell. Biol. 1995;15:4125-4135.

   Not in our library10.1128/mcb.15.8.4125

7. 7.

   Dhomen N, Marais R. BRAF signaling and targeted therapies in melanoma. Hematol. Oncol. Clin. North Am. 2009;23:529-545.

   Not in our library10.1016/j.hoc.2009.04.001

8. 8.

   Emery IF, Battelli C, Auclair PL, Carrier K, Hayes DM. Response to gefitinib and erlotinib in non-small cell lung cancer: a retrospective study. BMC Cancer. 2009;9:333.

   Not in our library10.1186/1471-2407-9-333

9. 9.

   Flaherty K, Puzanov I, Sosman J, Kim K, Ribas A, Mcarthur G, Lee RJ, Grippo JF, Nolop K, Chapman P. Phase I study of PLX4032: proof of concept for V600EBRAF mutation as a therapeutic target in human cancer. J. Clin. Oncol. 2009;27:15s.

   Not in our library

10. 10.

    Forbes SA, Bhamra G, Bamford S, Dawson E, Kok C, Clements J, Menzies A, Teague JW, Futreal PA, Stratton MR. The catalogue of somatic mutations in cancer (COSMIC). Curr. Protoc. Hum. Genet. 2008.

    Not in our library10.1002/0471142905.hg1011s57

11. 11.

    Garnett MJ, Rana S, Paterson H, Barford D, Marais R. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol. Cell. 2005;20:963-969.

    Not in our library10.1016/j.molcel.2005.10.022

12. 12.

    Halaban R, Krauthammer M, Pelizzola M, et al. Integrative analysis of epigenetic modulation in melanoma cell response to decitabine: clinical implications. PLoS ONE. 2009;4:e4563.

    Not in our library10.1371/journal.pone.0004563

13. 13.

    Hall-Jackson CA, Eyers PA, Cohen P, Goedert M, Boyle FT, Hewitt N, Plant H, Hedge P. Paradoxical activation of Raf by a novel Raf inhibitor. Chem. Biol. 1999;6:559-568.

    Not in our library10.1016/s1074-5521(99)80088-x

14. 14.

    Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature. 2010.

    Not in our library10.1038/nature08833

15. 15.
    Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF · 2010

    No notice
16. 16.

    Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J. Clin. Oncol. 2008;26:2046-2051.

    Not in our library10.1200/jco.2007.14.0707

17. 17.

    Hoek K, Rimm DL, Williams KR, et al. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res. 2004;64:5270-5282.

    Not in our library10.1158/0008-5472.can-04-0731

18. 18.

    Jiang X, Zhou J, Yuen NK, Corless CL, Heinrich MC, Fletcher JA, Demetri GD, Widlund HR, Fisher DE, Hodi FS. Imatinib targeting of KIT-mutant oncoprotein in melanoma. Clin. Cancer Res. 2008;14:7726-7732.

    Not in our library10.1158/1078-0432.ccr-08-1144

19. 19.

    King AJ, Patrick DR, Batorsky RS, et al. Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res. 2006;66:11100-11105.

    Not in our library10.1158/0008-5472.can-06-2554

20. 20.

    Laird AD, Morrison DK, Shalloway D. Characterization of Raf-1 activation in mitosis. J. Biol. Chem. 1999;274:4430-4439.

    Not in our library10.1074/jbc.274.7.4430

21. 21.

    Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Mol. Cell. 2002;9:945-956.

    Not in our library10.1016/s1097-2765(02)00519-1

22. 22.

    Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat. Rev. Mol. Cell Biol. 2005;6:56-68.

    Not in our library10.1038/nrm1549

23. 23.

    Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature. 2009;2:2.

    Not in our library10.1038/nature08314

24. 24.

    Rushworth LK, Hindley AD, O’neill E, Kolch W. Regulation and role of Raf-1/B-Raf heterodimerization. Mol. Cell. Biol. 2006;26:2262-2272.

    Not in our library10.1128/mcb.26.6.2262-2272.2006

25. 25.

    Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C. BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells. Mol. Cancer Res. 2008;6:751-759.

    Not in our library10.1158/1541-7786.mcr-07-2001

26. 26.

    Sharma SV, Settleman J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007;21:3214-3231.

    Not in our library10.1101/gad.1609907

27. 27.

    Smalley KS, Nathanson KL, Flaherty KT. Genetic subgrouping of melanoma reveals new opportunities for targeted therapy. Cancer Res. 2009;69:3241-3244.

    Not in our library10.1158/0008-5472.can-08-4305

28. 28.

    Tsai J, Lee JT, Wang W, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. U S A. 2008;105:3041-3046.

    Not in our library10.1073/pnas.0711741105

29. 29.

    Weinstein IB, Joe A. Oncogene addiction. Cancer Res. 2008;68:3077-3080.

    Not in our library10.1158/0008-5472.can-07-3293

Cited by papers we hold 5

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• Comparison of high resolution melting analysis, pyrosequencing, next generation sequencing and immunohistochemistry to conventional Sanger sequencing for the detection of p.V600E and non-p.V600E BRAFmutations · 2014
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• Intra- and Inter-Tumor Heterogeneity of BRAFV600EMutations in Primary and Metastatic Melanoma · 2012
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• The role of BRAF V600 mutation in melanoma · 2012
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• Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032 · 2010
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