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  • Review Article
  • Published:

PAK signalling during the development and progression of cancer

Nature Reviews Cancer volume 14, pages 13–25 (2014)Cite this article

Subjects

Key Points

  • There are two subgroups of p21-activated kinases (PAKs), which comprise three members each: group I (PAK1–3) and group II (PAK 4–6). New genetic models of PAK in mice and fish have shown the unique functions of the six PAK isoforms.

  • PAK expression and activity, in particular those of PAK1 and PAK4, are often upregulated in human tumours. Tumour cells with upregulated PAK tend to become dependent on PAK signalling.

  • In many cell types, PAKs positively regulate at least three key proliferative signalling pathways: ERK, AKT and WNT.

  • In addition to their roles in proliferation, PAKs also have important roles in promoting cell survival, invasion and metastasis, and angiogenesis.

  • Several potent and specific small-molecule inhibitors of all PAKs or of group I or II PAKs are in advanced stages of preclinical development. However, such agents will need to be used with caution, as PAK function may be required for maintaining vascular integrity.

  • Inhibitors that target PAKs may be useful in cancers that have amplified PAK alleles, as well as in cancers that depend on PAK for activation of downstream signalling pathways, such as ERBB2-amplified breast cancer and colon cancers that are driven by mutations in the WNT pathway.

Abstract

p21-activated kinases (PAKs) are positioned at the nexus of several oncogenic signalling pathways. Overexpression or mutational activation of PAK isoforms frequently occurs in various human tumours, and recent data suggest that excessive PAK activity drives many of the cellular processes that are the hallmarks of cancer. In this Review, we discuss the mechanisms of PAK activation in cancer, the key substrates that mediate the developmental and oncogenic effects of this family of kinases, and how small-molecule inhibitors of these enzymes might be best developed and deployed for the treatment of cancer.

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Figure 1: Validated PAK substrates and their roles in the hallmarks of cancer.
Figure 2: The role of PAK in growth signal autonomy and cell survival.
Figure 3: PAK signalling in angiogenesis and modulation of vascular permeability.
Figure 4: Specificity of PAK inhibitors.

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Acknowledgements

This work was supported by grants to J.C. from the US Department of Defence (W81XWH-06-1-0213) and the US National Institutes of Health (R01 CA58836, R01 CA098830, and R01 CA142928), and to the Fox Chase Cancer Center, Philadelphia, Pennsylvania (P30 CA006927), as well as by an appropriation from the state of Pennsylvania, USA.

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  1. Maria Radu, Galina Semenova and Rachelle Kosoff: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111, Pennsylvania, USA

    Maria Radu, Galina Semenova, Rachelle Kosoff & Jonathan Chernoff

  2. Cancer Biology program, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Rachelle Kosoff

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  1. Maria Radu
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Correspondence to Jonathan Chernoff.

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Radu, M., Semenova, G., Kosoff, R. et al. PAK signalling during the development and progression of cancer. Nat Rev Cancer 14, 13–25 (2014). https://doi.org/10.1038/nrc3645

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