Oncotarget

Research Papers:

Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970

Amy B. Hall, Dave Newsome, Yuxin Wang, Diane M. Boucher, Brenda Eustace, Yong Gu, Brian Hare, Mac A. Johnson, Howard Li, Sean Milton, Cheryl E. Murphy, Darin Takemoto, Crystal Tolman, Mark Wood, Peter Charlton, Jean-Damien Charrier, Brinley Furey, Julian Golec, Philip M. Reaper _ and John R. Pollard

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Oncotarget. 2014; 5:5674-5685. https://doi.org/10.18632/oncotarget.2158

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Abstract

Amy B. Hall1,*, Dave Newsome1,*, Yuxin Wang1,*, Diane M. Boucher1, Brenda Eustace1, Yong Gu1, Brian Hare1, Mac A. Johnson1, Howard Li1, Sean Milton1, Cheryl E. Murphy1, Darin Takemoto1, Crystal Tolman1, Mark Wood1, Peter Charlton2, Jean-Damien Charrier2, Brinley Furey1, Julian Golec2, Philip M. Reaper2 and John R. Pollard2

1 Vertex Pharmaceuticals Inc, Boston, MA, USA

2 Vertex Pharmaceuticals (Europe) Ltd, Milton Park, Abingdon, Oxfordshire, UK

* These authors contributed equally to this work

Correspondence:

John R Pollard , email:

Keywords: ATR, DNA damage response, VX-970

Received: June 9, 2014 Accepted: July 2, 2014 Published: July 3, 2014

Abstract

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.


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