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

Lookup NU author(s): Dr Martina Finetti, Dr Stephen Crosier, Dr Daniel Williamson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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) PDGFR alpha 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 PDGFR alpha inhibitor pazopanib are susceptible to FGFR inhibitors. We show that PDGFR alpha levels are regulated by SMARCB1 expression, and assessment of clinical specimens documents the expression of both PDGFR alpha and FGFR1 in rhabdoid tumor patients. Our findings support a therapeutic approach in cancers with SWI/SNF deficiencies by exploiting RTK coactivation dependencies.


Publication metadata

Author(s): Wong JP, Todd JR, Finetti MA, McCarthy F, Broncel M, Vyse S, Luczynski MT, Crosier S, Ryall KA, Holmes K, Payne LS, Daley F, Wai P, Jenks A, Tanos B, Tan AC, Natrajan RC, Williamson D, Huang PH

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2016

Volume: 17

Issue: 5

Pages: 1265-1275

Print publication date: 25/10/2016

Online publication date: 25/10/2016

Acceptance date: 30/09/2016

ISSN (print): 2211-1247

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.celrep.2016.10.005

DOI: 10.1016/j.celrep.2016.10.005


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