title: NUAK2 Amplification Coupled with PTEN Deficiency Promotes Melanoma Development via CDK Activation.
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.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. Department of Dermatology, Tokyo Medical and Dental University Graduate School and Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Namiki
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yaguchi
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. Department of Dermatology, Shinshu University School of Medicine, Matsumoto-shi, Nagano, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Valencia
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sergio G
authors.initials: SG
authors.lastname: Coelho
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Yin
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kawaguchi
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Wilfred D
authors.initials: WD
authors.lastname: Vieira
authors.affiliation: Research Institute for Clinical Oncology, Saitama Cancer Center, Kitaadachi, Saitama, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kaneko
authors.affiliation: Department of Dermatology, Osaka University Graduate School of Medicine, Suita-shi, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tanemura
authors.affiliation: Department of Dermatology, Osaka University Graduate School of Medicine, Suita-shi, Osaka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.affiliation: Department of Dermatology, Tokyo Medical and Dental University Graduate School and Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Yokozeki
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. yutakawa@z5.keio.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hearing
mesh_terms: D000368:Aged; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
chemical_list: D051357:Cyclin-Dependent Kinase 2; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011687:Purines; D000077546:Roscovitine; C486061:NUAK2 protein, human; C495894:CDK2 protein, human; C494929:PTEN protein, human
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