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Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma

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Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma Published OnlineFirst April 26, 2011; DOI: 10.1158/1541-7786.MCR-10-0512 Molecular Cancer Signaling and Regulation Research Phosphoproteomic Screen Identifies Potential Therapeutic Targets in Melanoma Kathryn Tworkoski1, Garima Singhal1, Sebastian Szpakowski2, Christina Ivins Zito1, Antonella Bacchiocchi3, Viswanathan Muthusamy3, Marcus Bosenberg3, Michael Krauthammer1, Ruth Halaban3, and David F. Stern1 Abstract Therapies directed against receptor tyrosine kinases are effective in many cancer subtypes, including lung and breast cancer. We used a phosphoproteomic platform to identify active receptor tyrosine kinases that might represent therapeutic targets in a panel of 25 melanoma cell strains. We detected activated receptors including TYRO3, AXL, MERTK, EPHB2, MET, IGF1R, EGFR, KIT, HER3, and HER4. Statistical analysis of receptor tyrosine kinase activation as well as ligand and receptor expression indicates that some receptors, such as FGFR3, may be activated via autocrine circuits. Short hairpin RNA knockdown targeting three of the active kinases identified in the screen, AXL, HER3, and IGF1R, inhibited the proliferation of melanoma cells and knockdown of active AXL also reduced melanoma cell migration. The changes in cellular phenotype observed on AXL knockdown seem to be modulated via the STAT3 signaling pathway, whereas the IGF1R-dependent alterations seem to be regulated by the AKT signaling pathway. Ultimately, this study identifies several novel targets for therapeutic intervention in melanoma. Mol Cancer Res; 9(6); 801–12. Ó2011 AACR. Introduction melanoma cell proliferation and survival (4–9). The use of RTK-directed therapeutics in melanoma has, however, Next generation cancer therapies that target receptor been limited by the lack of available information about tyrosine kinases (RTK) have a major impact on the dis- active RTKs in this disease. ease-free progression and survival of patients with breast To identify potential RTK therapeutic targets in mela- cancer and non–small cell lung carcinoma (NSCLC). RTK noma, we surveyed the expression of all 58 human RTKs inhibitors in clinical use include the antibodies trastuzumab and their agonists in a panel of 24 low-passage melanoma for HER2-positive breast cancer and cetuximab in epidermal cell strains and 1 commercially available melanoma cell line. growth factor receptor (EGFR)-positive colorectal cancer. The functional activation of 42 human RTKs was also Small molecule kinase inhibitors also target EGFR in examined and used to identify which RTKs are most NSCLC (Erlotinib), and KIT or platelet-derived growth frequently and intensely activated in melanoma. Short factor receptor (PDGFR) in gastrointestinal stromal tumors hairpin RNA (shRNA)-mediated knockdown of AXL, (Imatinib). HER3, and IGF1R, 3 of the RTKs identified in the screen, The incidence of melanoma has steadily risen in the resulted in decreased melanoma cell proliferation. AXL United States over the past 30 years, yet individuals with knockdown also reduced melanoma cell migration and late-stage melanoma have a median survival time of only these cellular responses seem to be regulated by the STAT3 9 months (1–3). Imatinib has been used to treat melanomas signaling pathway. These data identify new candidates for with mutationally activated KIT, whereas experimental therapeutic intervention in melanoma. studies show that targeting RTKs such as MET and insu- lin-like growth factor 1 receptor (IGF1R) may inhibit Materials and Methods Cell culture 1 2 Authors' Affiliations: Department of Pathology, Graduate Program in Yale University (YU)-designated and WW165 melanoma Computational Biology and Bioinformatics, and 3Department of Derma- tology, Yale University School of Medicine, New Haven, Connecticut cell strains were derived from primary and metastatic lesions Note: Supplementary data for this article are available at Molecular Cancer as described (10). Melanoma tumors were excised as part of Research Online (http://mcr.aacrjournals.org/). patient clinical care and were collected with the partici- G. Singhal, S. Szpakowski, and C.I. Zito contributed equally to the study. pants’ informed written consent according to HIPAA Corresponding Author: David F. Stern, BML 348 310 Cedar Street, New (Health Insurance Portability and Accountability Act) reg- Haven, CT 06510. Phone: 203-785-4832; Fax: 203-785-7467; E-mail: ulations with the approval of the Yale Human Investigation [email protected] Committee. Primary and metastatic melanoma cell strains doi: 10.1158/1541-7786.MCR-10-0512 were used prior to passage 20. Most melanoma cells were Ó2011 American Association for Cancer Research. cultured in OptiMEM (Invitrogen) supplemented with 5% www.aacrjournals.org 801 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst April 26, 2011; DOI: 10.1158/1541-7786.MCR-10-0512 Tworkoski et al. FBS and 1% penicillin/streptomycin (basal medium). The iScript cDNA Synthesis Kit from BioRad by using 0.8 mgof WW165 primary melanoma and YUHEIK mucosal mel- RNA per reaction. Universal TaqMan Master Mix (Applied anoma cells were grown in basal medium supplemented Biosystems) was used to conduct quantitative real-time with 0.1 mmol/L IBMX (3-isobutyl-1-methylxanthine; PCR (qRT-PCR) by using a 1 to 10 dilution of the resulting Sigma-Aldrich). Normal human melanocytes from new- cDNA. The following primers were used following the born foreskins (NBMEL) and discarded adult skin manufacturer's protocols: AXL (Hs0024357_m1), HER3 (RMP32F) were grown in basal medium supplemented (Hs00951455_m1), and glyceraldehyde 3 phosphate dehy- with 16 nmol/L 12-O-tetradecanoyl phorbol-13-acetate, drogenase (GAPDH; Hs99999905_m1; Applied Biosys- 0.1 mmol/L 3-isobutyl-1-methylxanthine, 2.5 nmol/L cho- tems). Relative mRNA expression was determined with the m 0 D lera toxin, 1 mol/L Na3VO4, and 0.1 mmol/L N6,2 -O- Ct method by using GAPDH as the reference gene. Gene dibutyryladenosine 30,50-cyclic monophosphate (Sigma- expression values for tumor RNAs were normalized to a Aldrich), termed TICVA (11). HEK293T cells from the negative control. A single RNA preparation was analyzed for American Type Culture Collection (ATCC) were grown in each microdissected tumor, and duplicates for each tumor Dulbecco's modified Eagle's medium containing 10% FBS, block. 1% penicillin/streptomycin, and 1% HEPES. MDA-MB- 231 cells, MDA-MB-453 cells, and BT474 cells (ATCC) Cell lysis, RTK arrays, immunoblotting, and were grown in RPMI containing 10% FBS and 1% hierarchical clustering penicillin/streptomycin. Where indicated, cells were starved in 0.1% serum prior to lysis, and pervanadate (50 mmol/L final) was added for 20 Gene expression analysis minutes before lysis. Cells were lysed in NP-40 lysis buffer Whole genome gene expression analysis was based on [1% NP-40, 150 mmol/L NaCl, 50 mmol/L Tris (pH 7.4), 5 data generated by the Yale SPORE in Skin Cancer (12). mmol/L EDTA, 10% glycerol with complete EDTA-free Briefly, NimbleGen human whole genome expression protease inhibitor tablets (Roche) and phosphatase inhibitor microarrays (array 2005-04-20_Human_60mer and array cocktails 1 and 2 (Sigma-Aldrich) added immediately before 2006-08-03_HG18_60mer) were used for hybridization cell lysis]. Cell lysates (250 mg) were analyzed with the Human of cDNA from normal melanocytes and melanoma cells Phospho-RTK Array Kit (R&D Systems); array maps at at NimbleGen Systems Iceland LLC, Vínlandsleið 2-4, http://www.rndsystems.com/pdf/ary001.pdf. Protein sam- 113 Reykjavik, Iceland (currently Roche Applied Science, ples were prepared for electrophoresis by addition of 5Â Basel, Switzerland) and by the Yale W.M. Keck Founda- Laemmli sample buffer, and immunoblotting was carried tion Biotechnology Resource as described (12). The out on nitrocellulose membranes blocked in 5% milk in microarray data from melanoma cell lines (YUCAS, Tris-buffered saline Tween-20 (1.5 mol/L NaCl, 0.2 mol/L YUCOT, YUDOSO, YUGOE, YUHEF, YUHUY, Tris-HCl, 0.05% Tween 20). Membranes were incubated YUKIM, YUKSI, YULAC, YUPLA, YUROB, YUROL, with antibodies in 5% milk or 5% bovine serum albumin YUSIV,YUTICA,YUZOR,WW165,andYUHEIK) overnight at 4C: anti-pHER3, anti-pIGF1R, anti-IGF1R, and 4 independent normal melanocytes cell cultures anti-pKIT, anti-MERTK, anti-pMET, anti-MET, anti- (NBMEL1-3 and RMP32F) were used to determine a pSTAT3, anti-STAT3, anti-pAKT, anti-AKT (Cell Signaling gene expression call (expressed/nonexpressed) and a mean Technology), anti-HER3, anti-GAPDH (Santa Cruz Bio- RTK expression value. An expression call threshold technology), anti-TYRO3 (Abcam), and anti-KIT (Dako). (761.0) was determined by Stat4 library in R. Briefly, Secondary antibodies conjugated to horseradish peroxidase parameters of a bimodal normal distribution were esti- were used at a 1:10,000 dilution for 1 hour at room tem- mated separating the gene expression intensity data into perature prior to development (Thermo Scientific). m ¼ m ¼ noise ( noise 279.9) and signal ( signal 2,360.6). Nonsupervised hierarchical clustering was done by manu- Genes were considered expressed if their observed inten- ally determined phospho-array data values ranging from 0 m À sity value (x)wasgreaterthanthe signal 1SDsignal (i.e., (background) to 5 (maximum phosphorylation; Tables 1 x > 761.0). To assess correlation between RTK activation and 2). Clustering of RTK data was done by Pearson's and ligand expression, we obtained a list of 473 known correlation with complete
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