Tailored therapeutic strategies for synovial sarcoma: receptor tyrosine kinase pathway analyses predict sensitivity to the mTOR inhibitor RAD001

Cancer Lett. 2014 May 28;347(1):114-22. doi: 10.1016/j.canlet.2014.01.027. Epub 2014 Jan 31.

Abstract

We examined efficacy of the mTOR inhibitor RAD001 to seek novel therapies for synovial sarcoma (SS). Although RAD001 had significant anti-tumor effects, its sensitivity differed among cell lines. Phospho-receptor tyrosine kinase (RTK) array analyses revealed c-MET phosphorylation in highly mTOR inhibitor-sensitive cells and PDGFRα (which induces intrinsic resistance to mTOR inhibitor) activation in less sensitive cells. Combined treatment with RAD001 and the PDGFR inhibitor pazopanib showed anti-tumor effects in xenograft models with less sensitive cells. Thus, evaluating activated RTKs in clinical samples may predict sensitivity to mTOR inhibitors, raising the possibility of a tailored therapy for SS.

Keywords: PDGFRα; RAD001; Receptor tyrosine kinase array; Synovial sarcoma; c-MET.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Division
  • Cell Line, Tumor
  • Everolimus
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors
  • Sarcoma, Synovial / drug therapy*
  • Sarcoma, Synovial / pathology
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • Antineoplastic Agents
  • Everolimus
  • MTOR protein, human
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Platelet-Derived Growth Factor alpha
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Sirolimus