title: Dual Targeting of PDGFRα and FGFR1 Displays Synergistic Efficacy in Malignant Rhabdoid Tumors.
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.
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Jocelyn P
authors: JP
authors: Wong
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Jason R
authors: JR
authors: Todd
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors: Martina A
authors: MA
authors: Finetti
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Frank
authors: F
authors: McCarthy
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Malgorzata
authors: M
authors: Broncel
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Simon
authors: S
authors: Vyse
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Maciej T
authors: MT
authors: Luczynski
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors: Stephen
authors: S
authors: Crosier
authors: Translational Bioinformatics and Cancer Systems Biology Laboratory, Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Karen A
authors: KA
authors: Ryall
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Kate
authors: K
authors: Holmes
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Leo S
authors: LS
authors: Payne
authors: The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Frances
authors: F
authors: Daley
authors: The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Patty
authors: P
authors: Wai
authors: Division of Cancer Therapeutics, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Andrew
authors: A
authors: Jenks
authors: Division of Cancer Therapeutics, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Barbara
authors: B
authors: Tanos
authors: Translational Bioinformatics and Cancer Systems Biology Laboratory, Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
authors: Aik-Choon
authors: AC
authors: Tan
authors: The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK.
authors: Rachael C
authors: RC
authors: Natrajan
authors: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK.
authors: Daniel
authors: D
authors: Williamson
authors: Division of Cancer Biology, The Institute of Cancer Research, London SW3 6JB, UK. Electronic address: paul.huang@icr.ac.uk.
authors: Paul H
authors: PH
authors: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000494:pharmacology; D009857:Oncogenes; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018335:Rhabdoid Tumor / Q000378:metabolism* / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology; D000077210:Sunitinib
chemical_list: D007191:Indazoles; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C516667:pazopanib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000069439:Dasatinib; D000077210:Sunitinib
keywords: FGFR1; PDGFRα; SMARCB1; SWI/SNF; pazopanib; receptor tyrosine kinase; rhabdoid tumor; signal transduction; tyrosine kinase inhibitor