Efficacy of ATR inhibitors as single agents in Ewing sarcoma.

Maria Nieto-Soler,Emilio Lecona,Daniel Azorin,Andres J Lopez-Contreras,Oscar Fernandez-Capetillo,Isabel Morgado-Palacin,Andre Nussenzweig,Elsa Callen,Javier Alonso,Vanesa Lafarga,Matilde Murga

doi:10.18632/oncotarget.11643

Abstract

Ewing sarcomas (ES) are pediatric bone tumors that arise from a driver translocation, most frequently EWS/FLI1. Current ES treatment involves DNA damaging agents, yet the basis for the sensitivity to these therapies remains unknown. Oncogene-induced replication stress (RS) is a known source of endogenous DNA damage in cancer, which is suppressed by ATR and CHK1 kinases. We here show that ES suffer from high endogenous levels of RS, rendering them particularly dependent on the ATR pathway. Accordingly, two independent ATR inhibitors show in vitro toxicity in ES cell lines as well as in vivo efficacy in ES xenografts as single agents. Expression of EWS/FLI1 or EWS/ERG oncogenic translocations sensitizes non-ES cells to ATR inhibitors. Our data shed light onto the sensitivity of ES to genotoxic agents, and identify ATR inhibitors as a potential therapy for Ewing Sarcomas.

Highlights

Genomic instability is widespread in cancer cells, as already noticed in the Boveri studies of the early 20th century [1]
Increased CHEK1 expression and/ or gene copy number gains have been observed in tumors with a high degree of genomic instability, which correlated with an increased sensitivity to ATR or CHK1 inhibition [21, 22]
To directly evaluate DNA replication in Ewing sarcomas (ES) cells, we analyzed replication fork progression on isolated stretched DNA fibers. These experiments revealed that fork progression is slower on any ES line tested (TC71, A673 and A4573) than in human primary retinal pigmentum epithelial (RPE) cells or in U2OS and SAOS osteosarcoma cell lines (Figure 1C)

Summary

Introduction

Genomic instability is widespread in cancer cells, as already noticed in the Boveri studies of the early 20th century [1]. As a consequence, targeting RS-response kinases ATR and CHK1 is preferentially toxic for tumors experiencing high levels of RS such as MYC-induced lymphomas, MLL-translocation driven leukemias or H-RAS driven fibrosarcomas [5,6,7]. In this context, the identification of cancers presenting high levels of RS is important to guide the use of ATR and CHK1 inhibitors in cancer therapy [8]

Methods

Results

Conclusion