Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs.
OBJECTIVE
Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive tumor type that is resistant to chemotherapy and there are no effective therapies. MPNSTs have been shown to have gene amplification for receptor tyrosine kinases (RTK), PDGFR and c-Kit. We tested the c-Kit inhibitor, imatinib, and PLX3397, a selective c-Fms and c-Kit inhibitor, to evaluate their efficacy against MPNST cells in vitro and in vivo.


METHODS
We tested the efficacy of imatinib or PLX3397 either alone or in combination with TORC1 inhibitor rapamycin in a cell proliferation assay in vitro and by immunoblotting to determine target inhibition. Immunoblotting and immunohistochemical analysis was further carried out using xenograft samples in vivo.


RESULTS
Our in vitro studies show that imatinib and PLX3397 similarly inhibit cell growth and this can be enhanced with rapamycin with comparable target specificity. However, in vivo studies clearly demonstrate that compared with imatinib, PLX3397 results in sustained blockade of c-Kit, c-Fms, and PDGFRβ, resulting in significant suppression of tumor growth. Moreover, staining for Iba-1, a marker for macrophages, indicates that PLX3397 results in significant depletion of macrophages in the growing tumors. The combination of PLX3397 and rapamycin results in even greater macrophage depletion with continued growth suppression, even when the drug treatment is discontinued.


CONCLUSIONS
Taken together, our data strongly suggest that PLX3397 is superior to imatinib in the treatment of MPNSTs, and the combination of PLX3397 with a TORC1 inhibitor could provide a new therapeutic approach for the treatment of this disease.
Authors' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York ppp2115@columbia.edu.
Parag P
PP
Patwardhan
Authors' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York.
Oliver
O
Surriga
Authors' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York.
Michael J
MJ
Beckman
Authors' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York.
Elisa
E
de Stanchina
Authors' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York.
Ronald P
RP
Dematteo
Authors' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York.
William D
WD
Tap
Authors' Affiliations: Jennifer Goodman Linn Laboratory of New Drug Development, Department of Medicine, Department of Molecular Pharmacology and Chemistry, Department of Surgery, Memorial Sloan Kettering Cancer Center; and Division of Hematology/Oncology, Columbia University Medical Center, New York, New York.
Gary K
GK
Schwartz
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009442:Neurilemmoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010879:Piperazines / Q000008:administration & dosage; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; C000600259:pexidartinib; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta; D020123:Sirolimus