NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation

Cancer Res. 2015 Jul 1;75(13):2708-15. doi: 10.1158/0008-5472.CAN-13-3209. Epub 2015 Apr 1.

Abstract

The AMPK-related kinase NUAK2 has been implicated in melanoma growth and survival outcomes, but its therapeutic utility has yet to be confirmed. In this study, we show how its genetic amplification in PTEN-deficient melanomas may rationalize the use of CDK2 inhibitors as a therapeutic strategy. Analysis of array-CGH data revealed that PTEN deficiency is coupled tightly with genomic amplification encompassing the NUAK2 locus, a finding strengthened by immunohistochemical evidence that phospho-Akt overexpression was correlated with NUAK2 expression in clinical specimens of acral melanoma. Functional studies in melanoma cells showed that inactivation of the PI3K pathway upregulated p21 expression and reduced the number of cells in S phase. NUAK2 silencing and inactivation of the PI3K pathway efficiently controlled CDK2 expression, whereas CDK2 inactivation specifically abrogated the growth of NUAK2-amplified and PTEN-deficient melanoma cells. Immunohistochemical analyses confirmed an association of CDK2 expression with NUAK2 amplification and p-Akt expression in melanomas. Finally, pharmacologic inhibition of CDK2 was sufficient to suppress the growth of NUAK2-amplified and PTEN-deficient melanoma cells in vitro and in vivo. Overall, our results show how CDK2 blockade may offer a promising therapy for genetically defined melanomas, where NUAK2 is amplified and PTEN is deleted.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / genetics
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Gene Amplification
  • Humans
  • Male
  • Melanoma / drug therapy
  • Melanoma / enzymology
  • Melanoma / genetics*
  • Melanoma / pathology
  • Mice
  • Mice, Nude
  • Middle Aged
  • Molecular Targeted Therapy
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / genetics*
  • Purines / pharmacology
  • Roscovitine
  • Signal Transduction
  • Skin Neoplasms / drug therapy
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology

Substances

  • Protein Kinase Inhibitors
  • Purines
  • Roscovitine
  • Phosphatidylinositol 3-Kinases
  • NUAK2 protein, human
  • Protein-Serine-Threonine Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • PTEN Phosphohydrolase
  • PTEN protein, human