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.
Bibliographical noteFunding Information:
This work was supported by grants from the Institute of Cancer Research (ICR) , Cancer Research UK ( C36478/A19281 ), Sarcoma UK ( 003.2014 ), Royal Marsden Cancer Charity , and Biotechnology and Biological Sciences Research Council (BBSRC) ( BB/I014276/I and BB/M013782/1 ) to P.H.H.; Breast Cancer Now ( SF01May2011 ) to R.C.N.; NIH ( T32CA17468 ) to K.A.R.; David F. and Margaret T. Grohne Family Foundation to A.-C.T.; and Children With Cancer UK ( 2012/134 ), North Eastern Children’s Cancer Research (NECCR) (NCC Core Grant Support) to D.W., whose work was undertaken within the remit of a Children’s Cancer and Leukaemia Group (CCLG) Biological Study 2012 BS 05 and as part of the INSTINCT network programme grant, co-funded by The Brain Tumour Charity , Great Ormond Street Children’s Charity , and Children With Cancer UK ( 16/193 ). The CHLA226 and BT12 cell lines were kindly provided by the Children’s Oncology Group Cell Culture Repository.
© 2016 The Author(s)
- receptor tyrosine kinase
- rhabdoid tumor
- signal transduction
- tyrosine kinase inhibitor
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)