RESUMO
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.
Assuntos
Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dasatinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Indazóis , Indóis/farmacologia , Oncogenes , Pirimidinas/farmacologia , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Sulfonamidas/farmacologia , SunitinibeRESUMO
Helicobacter pylori infection causes a broad spectrum of clinical diseases and the clinical manifestations of the infection depend on host, environmental, and bacterial factors. These factors have an impact on the pattern and severity of gastritis and ultimately determine the clinical outcome of H. pylori infection. Better staging of gastritis may help to identify patients at risk of gastric cancer. In this article we will examine the complex interaction between host, environmental, and bacterial factors in the pathogenesis of H. pylori infection.