Effects of Sunitinib and Other Kinase Inhibitors on Cells Harboring a PDGFRB Mutation Associated with Infantile Myofibromatosis.

Martin Sramek,Jaroslav Sterba,Hana Noskova,Kristyna Polaskova,Peter Mudry,Petra Macigova,Jakub Neradil,Renata Veselska,Ondrej Slaby

doi:10.3390/ijms19092599

Abstract

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.

Highlights

Infantile myofibromatosis (IM; [MIM#228550]) is a disorder of mesenchymal proliferation characterized by the development of nonmetastatic tumors [1] that present as firm, flesh-colored to purple nodules usually located in the skin, subcutaneous tissues, bone, muscle or visceral organs [2,3]
We demonstrate for the first time the efficacy of sunitinib, erlotinib, U0126 and FR180204 on the cell line harboring a c.1681C>T (p.R561C) PDGFRB mutation found in patients with IM
Germline Mutations in PDGFRB Were Identified in Both Children, and the Same Mutation in PDGFRB Was Confirmed in NSTS-47 Cells

Summary

Introduction

Infantile myofibromatosis (IM; [MIM#228550]) is a disorder of mesenchymal proliferation characterized by the development of nonmetastatic tumors [1] that present as firm, flesh-colored to purple nodules usually located in the skin, subcutaneous tissues, bone, muscle or visceral organs [2,3]. This disease was described under different names, the name “infantile myofibromatosis” was first used in 1981 [4]. The prognosis is excellent in solitary or multicentric nonvisceral forms with a possibility of spontaneous regression of the lesions but is poor when detected in the viscera [9]. Multiple lesions or surgically unresectable lesions are treated using various therapeutics, such as anti-inflammatory drugs, interferon-alpha, vinblastine, vincristine, dactinomycin, cyclophosphamide and methotrexate [6,8]

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