Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors

Oncogene volume 37, pages 944–952 (2018)Cite this article

Subjects

Abstract

Activating mutations in the RAC1 gene have recently been discovered as driver events in malignant melanoma. Expression of this gene is associated with melanocyte proliferation, and melanoma cells bearing this mutation are insensitive to BRAF inhibitors such as vemurafenib and dabrafenib, and also may evade immune surveillance due to enhanced expression of PD-L1. Activating mutations in RAC1 are of special interest, as small-molecule inhibitors for the RAC effector p21-activated kinase (PAK) are in late-stage clinical development and might impede oncogenic signaling from mutant RAC1. In this work, we explore the effects of PAK inhibition on RAC1P29S signaling in zebrafish embryonic development, in the proliferation, survival and motility of RAC1P29S-mutant human melanoma cells, and on tumor formation and progression from such cells in mice. We report that RAC1P29S evokes a Rasopathy-like phenotype on zebrafish development that can be blocked by inhibitors of PAK or MEK. We also found and that RAC1-mutant human melanoma cells are resistant to clinical inhibitors of BRAF but are uniquely sensitive to PAK inhibitors. These data suggest that suppressing the PAK pathway might be of therapeutic benefit in this type of melanoma.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. Davis MJ, Ha BH, Holman EC, Halaban R, Schlessinger J, Boggon TJ . RAC1P29S is a spontaneously activating cancer-associated GTPase. Proc Natl Acad Sci USA 2013; 110: 912–917.

    Article  CAS  Google Scholar 

  2. Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP et al. A landscape of driver mutations in melanoma. Cell 2012; 150: 251–263.

    Article  CAS  Google Scholar 

  3. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 2012; 44: 1006–1014.

    Article  CAS  Google Scholar 

  4. Watson IR, Li L, Cabeceiras PK, Mahdavi M, Gutschner T, Genovese G et al. The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. Cancer Res 2014; 74: 4845–4852.

    Article  CAS  Google Scholar 

  5. Vu HL, Rosenbaum S, Purwin TJ, Davies MA, Aplin AE . RAC1 P29S regulates PD-L1 expression in melanoma. Pigment Cell Melanoma Res 2015; 28: 590–598.

    Article  CAS  Google Scholar 

  6. Kawazu M, Ueno T, Kontani K, Ogita Y, Ando M, Fukumura K et al. Transforming mutations of RAC guanosine triphosphatases in human cancers. Proc Natl Acad Sci USA 2013; 110: 3029–3034.

    Article  CAS  Google Scholar 

  7. Qiu R-G, Chen J, Kirn D, McCormick F, Symons M . An essential role for Rac in Ras transformation. Nature 1995; 374: 457–459.

    Article  CAS  Google Scholar 

  8. Radu M, Semenova G, Kosoff R, Chernoff J . PAK signalling during the development and progression of cancer. Nat Rev Cancer 2014; 14: 13–25.

    Article  CAS  Google Scholar 

  9. Ong CC, Jubb AM, Jakubiak D, Zhou W, Rudolph J, Haverty PM et al. P21-activated kinase 1 (PAK1) as a therapeutic target in BRAF wild-type melanoma. J Natl Cancer Inst 2013; 105: 606–607.

    Article  CAS  Google Scholar 

  10. Chow HY, Jubb AM, Koch JN, Jaffer ZM, Stepanova D, Campbell DA et al. p21-activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model. Cancer Res 2012; 72: 5966–5975.

    Article  CAS  Google Scholar 

  11. Anastasaki C, Estep AL, Marais R, Rauen KA, Patton EE . Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. Hum Mol Genet 2009; 18: 2543–2554.

    Article  CAS  Google Scholar 

  12. Halaban R, Krauthammer M . RASopathy gene mutations in melanoma. J Invest Dermatol 2016; 136: 1755–1759.

    Article  CAS  Google Scholar 

  13. Jindal GA, Goyal Y, Burdine RD, Rauen KA, Shvartsman SY . RASopathies: unraveling mechanisms with animal models. Dis Model Mech 2015; 8: 769–782.

    Article  Google Scholar 

  14. Anastasaki C, Rauen KA, Patton EE . Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish. Dis Model Mech 2012; 5: 546–552.

    Article  CAS  Google Scholar 

  15. Ong CC, Gierke S, Pitt C, Sagolla M, Cheng CK, Zhou W et al. Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents. Breast Cancer Res 2015; 17: 59.

    Article  Google Scholar 

  16. Semenova G, Chernoff J . Targeting PAK1. Biochem Soc Trans 2017; 45: 79–88.

    Article  CAS  Google Scholar 

  17. Grzmil M, Whiting D, Maule J, Anastasaki C, Amatruda JF, Kelsh RN et al. The INT6 cancer gene and MEK signaling pathways converge during zebrafish development. PLoS One 2007; 2: e959.

    Article  Google Scholar 

  18. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y . Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA 2004; 101: 7618–7623.

    Article  CAS  Google Scholar 

  19. Halaban R . RAC1 and melanoma. Clin Ther 2015; 37: 682–685.

    Article  Google Scholar 

  20. Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N, Wu C et al. Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat Genet 2015; 47: 996–1002.

    Article  CAS  Google Scholar 

  21. Li A, Ma Y, Yu X, Mort RL, Lindsay CR, Stevenson D et al. Rac1 drives melanoblast organization during mouse development by orchestrating pseudopod-driven motility and cell-cycle progression. Dev Cell 2011; 21: 722–734.

    Article  CAS  Google Scholar 

  22. Fritsch R, de Krijger I, Fritsch K, George R, Reason B, Kumar MS et al. RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell 2013; 153: 1050–1063.

    Article  CAS  Google Scholar 

  23. Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 2014; 25: 831–845.

    Article  CAS  Google Scholar 

  24. Lindsay CR, Lawn S, Campbell AD, Faller WJ, Rambow F, Mort RL et al. P-Rex1 is required for efficient melanoblast migration and melanoma metastasis. Nat Commun 2011; 2: 555.

    Article  Google Scholar 

  25. Kimmel CB, Ballard WW, Kimmel SR, Ullmann B, Schilling TF . Stages of embryonic development of the zebrafish. Dev Dyn 1995; 203: 253–310.

    Article  CAS  Google Scholar 

  26. Shin JT, Priest JR, Ovcharenko I, Ronco A, Moore RK, Burns CG et al. Human-zebrafish non-coding conserved elements act in vivo to regulate transcription. Nucleic Acids Res 2005; 33: 5437–5445.

    Article  CAS  Google Scholar 

  27. Rhodes J, Amsterdam A, Sanda T, Moreau LA, McKenna K, Heinrichs S et al. Emi1 maintains genomic integrity during zebrafish embryogenesis and cooperates with p53 in tumor suppression. Mol Cell Biol 2009; 29: 5911–5922.

    Article  CAS  Google Scholar 

  28. Lightcap CM, Kari G, Arias-Romero LE, Chernoff J, Rodeck U, Williams JC . Interaction with LC8 is required for Pak1 nuclear import and is indispensable for zebrafish development. PLoS One 2009; 4: e6025.

    Article  Google Scholar 

  29. Link V, Shevchenko A, Heisenberg CP . Proteomics of early zebrafish embryos. BMC Dev Biol 2006; 6: 1.

    Article  Google Scholar 

  30. Limame R, Wouters A, Pauwels B, Fransen E, Peeters M, Lardon F et al. Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays. PLoS One 2012; 7: e46536.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Drs Ruth Halaban and Meenhard Herlyn for providing melanoma cell lines, and Dr Rebecca Burdine for Tg(cmlc2:EGFP) zebrafish, Genentech for providing Frax-1036 and the Fox Chase Cancer Center Animal Facility for assistance with zebrafish experiments. This work was supported by R01CA227184 (JC), NIH CORE Grant P30 CA006927, and an appropriation from the state of Pennsylvania to the Fox Chase Cancer Center.

Author information

Author notes

  1. D Araiza-Olivera

    Present address: 4Current address: Instituto de Química, Universidad Nacional Autonoma de México, México City, México.,

Authors and Affiliations

  1. Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    D Araiza-Olivera, Y Feng, G Semenova, T Y Prudnikova & J Chernoff

  2. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    G Semenova

  3. Blood Cell Development & Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA

    J Rhodes

Authors
  1. D Araiza-Olivera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Semenova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Y Prudnikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Rhodes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Chernoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Chernoff.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Araiza-Olivera, D., Feng, Y., Semenova, G. et al. Suppression of RAC1-driven malignant melanoma by group A PAK inhibitors. Oncogene 37, 944–952 (2018). https://doi.org/10.1038/onc.2017.400

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.400

This article is cited by

Search

Advanced search

Quick links