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

Abstract

Summary: 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. : Malignant rhabdoid tumors (MRTs) are pediatric cancers characterized by a deficiency in the SWI/SNF subunit SMARCB1. Wong et al. show that MRTs display coactivation of PDGFRα and FGFR1 and that dual blockade of these receptors induces apoptosis. These findings present therapeutic opportunities to exploit tyrosine kinase dependencies in cancers with SWI/SNF deficiencies. Keywords: signal transduction, receptor tyrosine kinase, rhabdoid tumor, tyrosine kinase inhibitor, SWI/SNF, SMARCB1, PDGFRα, FGFR1, pazopanib