Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors

Cell Rep. 2016 Oct 25;17(5):1265-1275. doi: 10.1016/j.celrep.2016.10.005.


Subunits of the SWI/SNF chromatin remodeling complex are mutated in a significant proportion of human cancers. Malignant rhabdoid tumors (MRTs) are lethal pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Here, we employ an integrated molecular profiling and chemical biology approach to demonstrate that the receptor tyrosine kinases (RTKs) PDGFRα and FGFR1 are coactivated in MRT cells and that dual blockade of these receptors has synergistic efficacy. Inhibitor combinations targeting both receptors and the dual inhibitor ponatinib suppress the AKT and ERK1/2 pathways leading to apoptosis. MRT cells that have acquired resistance to the PDGFRα inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFRα levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFRα and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies.

Keywords: FGFR1; PDGFRα; SMARCB1; SWI/SNF; pazopanib; receptor tyrosine kinase; rhabdoid tumor; signal transduction; tyrosine kinase inhibitor.

MeSH terms

  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Dasatinib / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Gene Expression Profiling
  • Humans
  • Indazoles
  • Indoles / pharmacology
  • Oncogenes
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors*
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Rhabdoid Tumor / metabolism*
  • Rhabdoid Tumor / pathology*
  • Sulfonamides / pharmacology
  • Sunitinib


  • Indazoles
  • Indoles
  • Pyrimidines
  • Pyrroles
  • Sulfonamides
  • pazopanib
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Platelet-Derived Growth Factor alpha
  • Dasatinib
  • Sunitinib