Cancer Cells with Alternative Lengthening of Telomeres Do Not Display a General Hypersensitivity to ATR Inhibition.

Katharina I Deeg,Caroline Bauer,Karsten Rippe,Inn Chung

doi:10.3389/fonc.2016.00186

Abstract

Telomere maintenance is a hallmark of cancer as it provides cancer cells with cellular immortality. A significant fraction of tumors uses the alternative lengthening of telomeres (ALT) pathway to elongate their telomeres and to gain an unlimited proliferation potential. Since the ALT pathway is unique to cancer cells, it represents a potentially valuable, currently unexploited target for anti-cancer therapies. Recently, it was proposed that ALT renders cells hypersensitive to ataxia telangiectasia- and RAD3-related (ATR) protein inhibitors (Flynn et al., Science 347, 273). Here, we measured the response of various ALT- or telomerase-positive cell lines to the ATR inhibitor VE-821. In addition, we compared the effect of the inhibitor on cell viability in isogenic cell lines, in which ALT was active or suppressed. In these experiments, a general ATR inhibitor sensitivity of cells with ALT could not be confirmed. We rather propose that the observed variations in sensitivity reflect differences between cell lines that are unrelated to ALT.

Highlights

Cancer cells need to maintain their telomeres to avoid cellular senescence and apoptosis induced by the replicative shortening of chromosome ends
A significant fraction of tumors elongates the telomeres by an alternative lengthening of telomeres (ALT) pathway that operates via DNA repair and recombination processes as reviewed previously [1, 2]
A recent study investigated telomerase-positive and ALT-positive osteosarcoma and lung cancer cell lines as well as glioma stem cell lines and reported that cells that employ the ALT pathway are hypersensitive to the inhibition of the protein kinase ataxia telangiectasia- and RAD3-related protein (ATR), one of the two main DNA damage checkpoint-activating kinases in human cells [3]

Summary

Introduction

Cancer cells need to maintain their telomeres to avoid cellular senescence and apoptosis induced by the replicative shortening of chromosome ends. A recent study investigated telomerase-positive and ALT-positive osteosarcoma and lung cancer cell lines as well as glioma stem cell lines and reported that cells that employ the ALT pathway are hypersensitive to the inhibition of the protein kinase ataxia telangiectasia- and RAD3-related protein (ATR), one of the two main DNA damage checkpoint-activating kinases in human cells [3]. The authors concluded that treatment with the ATR inhibitor VE-821 selectively kills ALT cells within 6 days. They proposed that the immediate cell death induced by ATR inhibition in ALT cells is caused by an accumulation of DNA damage, aberrant anaphase chromosome

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Conclusion