Infantile myofibromatosis represents one of the most common proliferative fibrous tumors of infancy and childhood. More effective treatment is needed for drug-resistant patients, and targeted therapy using specific protein kinase inhibitors could be a promising strategy. To date, several studies have confirmed a connection between the p.R561C mutation in gene encoding platelet-derived growth factor receptor beta (PDGFR-beta) and the development of infantile myofibromatosis. This study aimed to analyze the phosphorylation of important kinases in the NSTS-47 cell line derived from a tumor of a boy with infantile myofibromatosis who harbored the p.R561C mutation in PDGFR-beta. The second aim of this study was to investigate the effects of selected protein kinase inhibitors on cell signaling and the proliferative activity of NSTS-47 cells. We confirmed that this tumor cell line showed very high phosphorylation levels of PDGFR-beta, extracellular signal-regulated kinases (ERK) 1/2 and several other protein kinases. We also observed that PDGFR-beta phosphorylation in tumor cells is reduced by the receptor tyrosine kinase inhibitor sunitinib. In contrast, MAPK/ERK kinases (MEK) 1/2 and ERK1/2 kinases remained constitutively phosphorylated after treatment with sunitinib and other relevant protein kinase inhibitors. Our study showed that sunitinib is a very promising agent that affects the proliferation of tumor cells with a p.R561C mutation in PDGFR-beta.

Central European Institute of Technology Masaryk University 62500 Brno Czech Republic

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University 66263 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic

Laboratory of Tumor Biology Department of Experimental Biology Faculty of Science Masaryk University 61137 Brno Czech Republic

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Martignetti J.A., Tian L., Li D., Ramirez M.C., Camacho-Vanegas O., Camacho S.C., Guo Y., Zand D.J., Bernstein A.M., Masur S.K., et al. Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am. J. Hum. Genet. 2013;92:1001–1007. doi: 10.1016/j.ajhg.2013.04.024. PubMed DOI PMC

Levine E., Fréneaux P., Schleiermacher G., Brisse H., Pannier S., Teissier N., Mesples B., Orbach D. Risk-adapted therapy for infantile myofibromatosis in children. Pediatr. Blood Cancer. 2012;59:115–120. doi: 10.1002/pbc.23387. PubMed DOI

Kim E.J., Wang K.C., Lee J.Y., Phi J.H., Park S.H., Cheon J.E., Jang Y.E., Kim S.K. Congenital solitary infantile myofibromatosis involving the spinal cord. J. Neurosurg. Pediatr. 2013;11:82–86. doi: 10.3171/2012.9.PEDS12245. PubMed DOI

Venkatesh V., Kumar B.P., Kumar K.A., Mohan A.P. Myofibroma-a rare entity with unique clinical presentation. J. Maxillofac. Oral Surg. 2015;14:64–68. doi: 10.1007/s12663-011-0299-5. PubMed DOI PMC

Hausbrandt P.A., Leithner A., Beham A., Bodo K., Raith J., Windhager R. A rare case of infantile myofibromatosis and review of literature. J. Pediatr. Orthop. B. 2010;19:122–126. doi: 10.1097/BPB.0b013e32832e4756. PubMed DOI

Weaver M.S., Navid F., Huppmann A., Meany H., Angiolillo A. Vincristine and Dactinomycin in Infantile Myofibromatosis with a Review of Treatment Options. J. Pediatr. Hematol. Oncol. 2015;37:237–241. doi: 10.1097/MPH.0000000000000286. PubMed DOI

Cheung Y.H., Gayden T., Campeau P.M., LeDuc C.A., Russo D., Nguyen V.H., Guo J., Qi M., Guan Y., Albrecht S., et al. A recurrent PDGFRB mutation causes familial infantile myofibromatosis. Am. J. Hum. Genet. 2013;92:996–1000. doi: 10.1016/j.ajhg.2013.04.026. PubMed DOI PMC

Mudry P., Slaby O., Neradil J., Soukalova J., Melicharkova K., Rohleder O., Jezova M., Seehofnerova A., Michu E., Veselska R., et al. Case report: Rapid and durable response to PDGFR targeted therapy in a child with refractory multiple infantile myofibromatosis and a heterozygous germline mutation of the PDGFRB gene. BMC Cancer. 2017;17:119. doi: 10.1186/s12885-017-3115-x. PubMed DOI PMC

Gatibelza M.E., Vazquez B.R., Bereni N., Denis D., Bardot J., Degardin N. Isolated infantile myofibromatosis of the upper eyelid: Uncommon localization and long-term results after surgical management. J. Pediatr. Surg. 2012;47:1457–1459. doi: 10.1016/j.jpedsurg.2012.03.092. PubMed DOI

Murray N., Hanna B., Graf N., Fu H., Mylene V., Campeau P.M., Ronan A. The spectrum of infantile myofibromatosis includes both non-penetrance and adult recurrence. Eur. J. Med. Genet. 2017;60:353–358. doi: 10.1016/j.ejmg.2017.02.005. PubMed DOI

Lepelletier C., Al-Sarraj Y., Bodemer C., Shaath H., Fraitag S., Kambouris M., Hamel-Teillac D., Shanti H.E., Hadj-Rabia S. Heterozygous PDGFRB Mutation in a Three-generation Family with Autosomal Dominant Infantile Myofibromatosis. Acta Derm. Venereol. 2017;97:858–859. doi: 10.2340/00015555-2671. PubMed DOI

Heldin C.H. Targeting the PDGF signaling pathway in tumor treatment. Cell. Commun. Signal. 2013;11:97. doi: 10.1186/1478-811X-11-97. PubMed DOI PMC

Cao Y. Multifarious functions of PDGFs and PDGFRs in tumor growth and metastasis. Trends Mol. Med. 2013;19:460–473. doi: 10.1016/j.molmed.2013.05.002. PubMed DOI

Andrae J., Gallini R., Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22:1276–1312. doi: 10.1101/gad.1653708. PubMed DOI PMC

Hoch R.V., Soriano P. Roles of PDGF in animal development. Development. 2003;130:4769–4784. doi: 10.1242/dev.00721. PubMed DOI

Aster J.C., Pear W.S., Blacklow S.C. The Varied Roles of Notch in Cancer. Annu. Rev. Pathol. 2017;12:245–275. doi: 10.1146/annurev-pathol-052016-100127. PubMed DOI PMC

Jin S., Hansson E.M., Tikka S., Lanner F., Sahlgren C., Farnebo F., Baumann M., Kalimo H., Lendahl U. Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ. Res. 2008;102:1483–1491. doi: 10.1161/CIRCRESAHA.107.167965. PubMed DOI

Linhares N.D., Freire M.C., Cardenas R.G., Pena H.B., Bahia M., Pena S.D. Exome sequencing identifies a novel homozygous variant in NDRG4 in a family with infantile myofibromatosis. Eur. J. Med. Genet. 2014;57:643–648. doi: 10.1016/j.ejmg.2014.08.010. PubMed DOI

Linhares N.D., Freire M.C., Cardenas R.G., Bahia M., Puzenat E., Aubin F., Pena S.D. Modulation of expressivity in PDGFRB-related infantile myofibromatosis: A role for PTPRG? Genet. Mol. Res. 2014;13:6287–6292. doi: 10.4238/2014.August.15.11. PubMed DOI

Mirenda M., Toffali L., Montresor A., Scardoni G., Sorio C., Laudanna C. Protein tyrosine phosphatase receptor type γ is a JAK phosphatase and negatively regulates leukocyte integrin activation. J. Immunol. 2015;194:2168–2179. doi: 10.4049/jimmunol.1401841. PubMed DOI

Arts F.A., Chand D., Pecquet C., Velghe A., Constantinescu S., Hallberg B., Demoulin J.B. PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. Oncogene. 2016;35:3239–3248. doi: 10.1038/onc.2015.383. PubMed DOI

Faivre S., Demetri G., Sargent W., Raymond E. Molecular basis for sunitinib efficacy and future clinical development. Nat. Rev. Drug Discov. 2007;6:734–745. doi: 10.1038/nrd2380. PubMed DOI

Sos M.L., Koker M., Weir B.A., Heynck S., Rabinovsky R., Zander T., Seeger J.M., Weiss J., Fischer F., Frommolt P., et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 2009;69:3256–3261. doi: 10.1158/0008-5472.CAN-08-4055. PubMed DOI PMC

Yap J.L., Worlikar S., MacKerell A.D., Shapiro P., Fletcher S. Small-molecule inhibitors of the ERK signaling pathway: Towards novel anticancer therapeutics. ChemMedChem. 2011;6:38–48. doi: 10.1002/cmdc.201000354. PubMed DOI PMC

Abouantoun T.J., Castellino R.C., MacDonald T.J. Sunitinib induces PTEN expression and inhibits PDGFR signaling and migration of medulloblastoma cells. J. Neurooncol. 2011;101:215–226. doi: 10.1007/s11060-010-0259-9. PubMed DOI PMC

Wetmore C., Daryani V.M., Billups C.A., Boyett J.M., Leary S., Tanos R., Goldsmith K.C., Stewart C.F., Blaney S.M., Gajjar A. Phase II evaluation of sunitinib in the treatment of recurrent or refractory high-grade glioma or ependymoma in children: A children’s Oncology Group Study ACNS1021. Cancer Med. 2016;5:1416–1424. doi: 10.1002/cam4.713. PubMed DOI PMC

Jakacki R.I., Hamilton M., Gilbertson R.J., Blaney S.M., Tersak J., Krailo M.D., Ingle A.M., Voss S.D., Dancey J.E., Adamson P.C. Pediatric phase I and pharmacokinetic study of erlotinib followed by the combination of erlotinib and temozolomide: A Children’s Oncology Group Phase I Consortium Study. J. Clin. Oncol. 2008;26:4921–4927. doi: 10.1200/JCO.2007.15.2306. PubMed DOI PMC

Altomare D.A., Testa J.R. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24:7455–7464. doi: 10.1038/sj.onc.1209085. PubMed DOI

McCubrey J.A., Steelman L.S., Chappell W.H., Abrams S.L., Wong E.W., Chang F., Lehmann B., Terrian D.M., Milella M., Tafuri A., et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim. Biophys. Acta. 2007;1773:1263–1284. doi: 10.1016/j.bbamcr.2006.10.001. PubMed DOI PMC

Veselska R., Kuglik P., Cejpek P., Svachova H., Neradil J., Loja T., Relichova J. Nestin expression in the cell lines derived from glioblastoma multiforme. BMC Cancer. 2006;6:32. doi: 10.1186/1471-2407-6-32. PubMed DOI PMC

Schneider C.A., Rasband W.S., Eliceiri K.W. NIH Image to ImageJ: 25 Years of image analysis. Nat. Methods. 2012;9:671–675. doi: 10.1038/nmeth.2089. PubMed DOI PMC

Skoda J., Neradil J., Zitterbart K., Sterba J., Veselska R. EGFR signaling in the HGG-02 glioblastoma cell line with an unusual loss of EGFR gene copy. Oncol. Rep. 2014;31:480–487. doi: 10.3892/or.2013.2864. PubMed DOI

Schmittgen T.D., Livak K.J. Analyzing real-time PCR data by the comparative C(T) method. Nat. Protoc. 2008;3:1101–1108. doi: 10.1038/nprot.2008.73. PubMed DOI

New Target for Precision Medicine Treatment of Giant-Cell Tumor of Bone: Sunitinib Is Effective in the Treatment of Neoplastic Stromal Cells with Activated PDGFRβ Signaling