期刊
CELL REPORTS
卷 17, 期 5, 页码 1265-1275出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.10.005
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资金
- Institute of Cancer Research (ICR)
- Cancer Research UK [C36478/A19281]
- Sarcoma UK [003.2014]
- Royal Marsden Cancer Charity
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/I014276/I, BB/M013782/1]
- Breast Cancer Now
- NIH [T32CA17468]
- David F. and Margaret T. Grohne Family Foundation
- Children With Cancer UK [2012/134, 16/193]
- North Eastern Children's Cancer Research (NECCR) (NCC Core Grant Support)
- INSTINCT network programme grant
- Brain Tumour Charity
- Great Ormond Street Children's Charity
- Biotechnology and Biological Sciences Research Council [BB/M013782/1, BB/I014276/1] Funding Source: researchfish
- Children with Cancer UK [12-134] Funding Source: researchfish
- Sarcoma UK [SUK03.2014] Funding Source: researchfish
- The Brain Tumour Charity [16/193] Funding Source: researchfish
- BBSRC [BB/M013782/1, BB/I014276/1] Funding Source: UKRI
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.
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