PLX3397 treatment inhibits constitutive CSF1R-induced oncogenic ERK signaling, reduces tumor growth, and metastatic burden in osteosarcoma

Branden A. Smeester, Nicholas J. Slipek, Emily J. Pomeroy, Kanut Laoharawee, Sara H. Osum, Alex T. Larsson, Kyle B. Williams, Natalie Stratton, Kenta Yamamoto, Joseph J. Peterson, Susan K. Rathe, Lauren J. Mills, Wendy A. Hudson, Margaret R. Crosby, Minjing Wang, Eric P. Rahrmann, Branden S. Moriarity, David A. Largaespada

Research output: Contribution to journalArticle

Abstract

Osteosarcoma (OSA) is a heterogeneous and aggressive solid tumor of the bone. We recently identified the colony stimulating factor 1 receptor (Csf1r) gene as a novel driver of osteosarcomagenesis in mice using the Sleeping Beauty (SB) transposon mutagenesis system. Here, we report that a CSF1R-CSF1 autocrine/paracrine signaling mechanism is constitutively activated in a subset of human OSA cases and is critical for promoting tumor growth and contributes to metastasis. We examined CSF1R and CSF1 expression in OSAs. We utilized gain-of-function and loss-of-function studies (GOF/LOF) to evaluate properties of cellular transformation, downstream signaling, and mechanisms of CSF1R-CSF1 action. Genetic perturbation of CSF1R in immortalized osteoblasts and human OSA cell lines significantly altered oncogenic properties, which were dependent on the CSF1R-CSF1 autocrine/paracrine signaling. These functional alterations were associated with changes in the known CSF1R downstream ERK effector pathway and mitotic cell cycle arrest. We evaluated the recently FDA-approved CSF1R inhibitor Pexidartinib (PLX3397) in OSA cell lines in vitro and in vivo in cell line and patient-derived xenografts. Pharmacological inhibition of CSF1R signaling recapitulated the in vitro genetic alterations. Moreover, in orthotopic OSA cell line and subcutaneous patient-derived xenograft (PDX)-injected mouse models, PLX3397 treatment significantly inhibited local OSA tumor growth and lessened metastatic burden. In summary, CSF1R is utilized by OSA cells to promote tumorigenesis and may represent a new molecular target for therapy.

Original languageEnglish (US)
Article number115353
JournalBone
Volume136
DOIs
StatePublished - Jul 2020

Keywords

  • CSF1R
  • Osteosarcoma
  • PLX3397

PubMed: MeSH publication types

  • Journal Article

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