title: Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970.
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.
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA; These authors contributed equally to this work.
authors.forename: Amy B
authors.initials: AB
authors.lastname: Hall
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA; These authors contributed equally to this work.
authors.forename: Dave
authors.initials: D
authors.lastname: Newsome
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA; These authors contributed equally to this work.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Boucher
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Eustace
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Hare
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Mac A
authors.initials: MA
authors.lastname: Johnson
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Milton
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Murphy
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Darin
authors.initials: D
authors.lastname: Takemoto
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Crystal
authors.initials: C
authors.lastname: Tolman
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wood
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd, Milton Park, Abingdon, Oxfordshire.
authors.forename: Peter
authors.initials: P
authors.lastname: Charlton
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd, Milton Park, Abingdon, Oxfordshire.
authors.forename: Jean-Damien
authors.initials: JD
authors.lastname: Charrier
authors.affiliation: Vertex Pharmaceuticals Inc, Boston, MA, USA.
authors.forename: Brinley
authors.initials: B
authors.lastname: Furey
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd, Milton Park, Abingdon, Oxfordshire.
authors.forename: Julian
authors.initials: J
authors.lastname: Golec
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd, Milton Park, Abingdon, Oxfordshire.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Reaper
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd, Milton Park, Abingdon, Oxfordshire.
authors.forename: John R
authors.initials: JR
authors.lastname: Pollard
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D007555:Isoxazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D004247:DNA; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000598331:berzosertib; D002945:Cisplatin