title: Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR.
abstract: Oncogenic Ras and p53 loss-of-function mutations are common in many advanced sporadic malignancies and together predict a limited responsiveness to conventional chemotherapy. Notably, studies in cultured cells have indicated that each of these genetic alterations creates a selective sensitivity to ataxia telangiectasia and Rad3-related (ATR) pathway inhibition. Here, we describe a genetic system to conditionally reduce ATR expression to 10% of normal levels in adult mice to compare the impact of this suppression on normal tissues and cancers in vivo. Hypomorphic suppression of ATR minimally affected normal bone marrow and intestinal homeostasis, indicating that this level of ATR expression was sufficient for highly proliferative adult tissues. In contrast, hypomorphic ATR reduction potently inhibited the growth of both p53-deficient fibrosarcomas expressing H-rasG12V and acute myeloid leukemias (AMLs) driven by MLL-ENL and N-rasG12D. Notably, DNA damage increased in a greater-than-additive fashion upon combining ATR suppression with oncogenic stress (H-rasG12V, K-rasG12D, or c-Myc overexpression), indicating that this cooperative genome-destabilizing interaction may contribute to tumor selectivity in vivo. This toxic interaction between ATR suppression and oncogenic stress occurred without regard to p53 status. These studies define a level of ATR pathway inhibition in which the growth of malignancies harboring oncogenic mutations can be suppressed with minimal impact on normal tissue homeostasis, highlighting ATR inhibition as a promising therapeutic strategy.
authors: Abramson Family Cancer Research Institute and Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
authors: David W
authors: DW
authors: Schoppy
authors: Ryan L
authors: RL
authors: Ragland
authors: Oren
authors: O
authors: Gilad
authors: Nishita
authors: N
authors: Shastri
authors: Ashley A
authors: AA
authors: Peters
authors: Matilde
authors: M
authors: Murga
authors: Oscar
authors: O
authors: Fernandez-Capetillo
authors: J Alan
authors: JA
authors: Diehl
authors: Eric J
authors: EJ
authors: Brown
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D004249:DNA Damage; D005354:Fibrosarcoma / Q000235:genetics / Q000628:therapy; D016158:Genes, p53; D011905:Genes, ras; D006706:Homeostasis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000628:therapy; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D009857:Oncogenes; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D018797:Cell Cycle Proteins; D012333:RNA, Messenger; C576897:Atr protein, mouse; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases