Format

Send to

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

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

Author information

1
Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
2
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
3
Translational Bioinformatics and Cancer Systems Biology Laboratory, Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
4
The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK.
5
Division of Cancer Therapeutics, The Institute of Cancer Research, London SW3 6JB, UK.
6
Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: paul.huang@icr.ac.uk.

Abstract

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

PMID:
27783942
PMCID:
PMC5098123
DOI:
10.1016/j.celrep.2016.10.005
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center