title: A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function.
abstract: Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content γ-H2AX assay. Cancers with inactivating ATM mutations exhibit impaired DNA double-stranded break (DSB) repair and rely on compensatory repair pathways for survival. Therefore, impairing ATR activity may selectively sensitize cancer cells to killing. ATR inhibition in an ATM-deficient context results in phosphorylation of DNA-dependent protein kinase catalytic subunits (DNA-PKcs) and leads to induction of γ-H2AX. Using both in vitro and in vivo models, ATR inhibition enhanced efficacy in ATM loss-of-function mantle cell lymphoma (MCL) compared with ATM wild-type cancer cells. In summary, single-agent ATR inhibitors have therapeutic utility in the treatment of cancers, like MCL, in which ATM function has been lost.
  
  
  CONCLUSIONS
  These data suggest that single-agent ATR inhibitors have therapeutic utility and that ATR uses a complex and coordinated set of proteins to maintain genomic stability that could be further exploited.
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California. lorenataricani@yahoo.com dmenezes1@gmail.com.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Menezes
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Jenny
authors.initials: J
authors.lastname: Holt
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Feng
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Barsanti
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Yue
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Majid
authors.initials: M
authors.lastname: Ghoddusi
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Holash
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California.
authors.forename: Emma
authors.initials: E
authors.lastname: Lees
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California. lorenataricani@yahoo.com dmenezes1@gmail.com.
authors.forename: Lorena
authors.initials: L
authors.lastname: Taricani
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000096:biosynthesis*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009025:Morpholines / Q000008:administration & dosage; D009154:Mutation; D034741:RNA, Small Interfering; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; D002867:Chromones; C468783:H2AX protein, human; D006657:Histones; D009025:Morpholines; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins