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

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.

Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy

“…In vitro assays of PDGFRB protein activity have demonstrated significant increased kinase activity with several pathogenic variants (i.e., p.Arg561Cys, p.Asn666Lys) compared to wild type. The overactivity can be partly corrected by tyrosine kinase inhibitors such as imatinib and sumatinib (Arts et al, 2016; Sramek et al, 2018), providing strong rationale for treatment trials. In one report, an infant with numerous myofibromas and a germline PDGFRB p.Arg561Cys mutation had a rapid and durable response to combined therapy with sumitinib and vinblastine, as did his affected older sister (Mudry et al, 2017).…”

Diverse presentation and tailored treatment of infantile myofibromatosis: A single‐center experience

“…Genetic consultation is recommended, since mutations in PDGFRB and neurogenic locus notch homolog protein 3 (NOTCH3) have recently been found as the genetic causes for autosomal dominant IM in both familial and sporadic cases of IM 42–45 . Study of the PDGFRB/NOTCH3 pathways might offer new opportunities to understand the mechanisms of both tumor growth and regression in IM, as well as offer targeted therapeutic possibilities 45–47 . PDGFR‐targeted therapy might also be used in cases of refractory generalized IM 48 .…”

Novel PDGFRB rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib

“…For those complex cases, systemic chemotherapy, including the use of vinblastine and methotrexate and other “low dose” cytotoxic agents, has demonstrated activity (Azzam et al 2009; Weaver et al 2015). The recognition that most cases of IM are associated with either somatic or germline mutations activating the PDGFRβ kinase has suggested the potential clinical utility of treatment using molecularly targeted agents, such as sunitinib and other kinase inhibitors (Arts et al 2016; Agaimy et al 2017; Sramek et al 2018). It is therefore important to recognize more complicated rearrangements such as that seen in our patient as a potential mechanism by which PDGFRβ can be activated and subsequently targeted by molecular therapies.…”