NUAK2 amplification coupled with PTEN deficiency promote melanoma development via CDK activation

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 amplication 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 inactivaiton 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. Lastly, pharmacological 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 identify show how CDK2 blockade may offer a promising therapy for genetically-defined melanomas where NUAK2 is amplified and PTEN is deleted.