title: Combinatorial therapeutic targeting of BMP2 and MEK-ERK pathways in NF1-associated malignant peripheral nerve sheath tumors.
abstract: The clinical management of malignant peripheral nerve sheath tumors (MPNSTs) is challenging not only due to its aggressive and invasive nature, but also limited therapeutic options. Using gene expression profiling, our lab identified BMP2-SMAD1/5/8 pathway as a potential therapeutic target for treating MPNSTs. In this study, we explored the therapeutic impact of targeting BMP2-SMAD1/5/8 pathway in conjunction with RAS-MEK-ERK signaling, which is constitutively activated in MPNSTs. Our results indicated that single agent treatment with LDN-193189, a BMP2 Type I receptor inhibitor, did not affect the growth and survival of MPNST cells at biochemically relevant inhibitory concentrations. However, addition of a MEK1/2 inhibitor, selumetinib, to LDN-193189-treated cells resulted in significant inhibition of cell growth and induction of cell death. LDN-193189 at biochemically effective concentrations significantly inhibited motility and invasiveness of MPNST cells, and these effects were enhanced by the addition of selumetinib. Overall, our results advocate for a combinatorial therapeutic approach for MPNSTs that not only targets the growth and survival via inhibition of MEK1/2, but also its malignant spread by suppressing the activation of BMP2-SMAD1/5/8 pathway. Importantly, these studies were conducted in low-passage patient-derived MPNST cells, allowing for an investigation of the effects of the proposed drug treatments in a biologically-relevant context.
authors: Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA.|Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.|Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors: Sidra
authors: S
authors: Ahsan
authors: Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.|Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors: Yubin
authors: Y
authors: Ge
authors: Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA.|Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.|Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.|Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors: Michael A
authors: MA
authors: Tainsky
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000628:therapy*; D025542:Neurofibromin 1 / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C517975:AZD 6244; C525718:BMP2 protein, human; D001562:Benzimidazoles; D055396:Bone Morphogenetic Protein 2; C554430:LDN 193189; D025542:Neurofibromin 1; D011720:Pyrazoles; D011743:Pyrimidines; D048049:Extracellular Signal-Regulated MAP Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II; D048369:MAP Kinase Kinase 1
keywords: BMP2; cell signaling; combinatorial targeted therapy; malignant peripheral nerve sheath tumors; neurofibromatosis type 1