title: RPA inhibition increases replication stress and suppresses tumor growth.
abstract: The ATR/Chk1 pathway is a critical surveillance network that maintains genomic integrity during DNA replication by stabilizing the replication forks during normal replication to avoid replication stress. One of the many differences between normal cells and cancer cells is the amount of replication stress that occurs during replication. Cancer cells with activated oncogenes generate increased levels of replication stress. This creates an increased dependency on the ATR/Chk1 pathway in cancer cells and opens up an opportunity to preferentially kill cancer cells by inhibiting this pathway. In support of this idea, we have identified a small molecule termed HAMNO ((1Z)-1-[(2-hydroxyanilino)methylidene]naphthalen-2-one), a novel protein interaction inhibitor of replication protein A (RPA), a protein involved in the ATR/Chk1 pathway. HAMNO selectively binds the N-terminal domain of RPA70, effectively inhibiting critical RPA protein interactions that rely on this domain. HAMNO inhibits both ATR autophosphorylation and phosphorylation of RPA32 Ser33 by ATR. By itself, HAMNO treatment creates DNA replication stress in cancer cells that are already experiencing replication stress, but not in normal cells, and it acts synergistically with etoposide to kill cancer cells in vitro and slow tumor growth in vivo. Thus, HAMNO illustrates how RPA inhibitors represent candidate therapeutics for cancer treatment, providing disease selectivity in cancer cells by targeting their differential response to replication stress. Cancer Res; 74(18); 5165-72. ©2014 AACR.
authors: Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors: Jason G
authors: JG
authors: Glanzer
authors: Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors: Shengqin
authors: S
authors: Liu
authors: Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors: Ling
authors: L
authors: Wang
authors: Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska.
authors: Adam
authors: A
authors: Mosel
authors: Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska. Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska.
authors: Aimin
authors: A
authors: Peng
authors: Department of Oral Biology, University of Nebraska Medical Center, Omaha, Nebraska. Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska. goakley@unmc.edu.
authors: Greg G
authors: GG
authors: Oakley
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009281:Naphthalenes / Q000494:pharmacology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D051716:Replication Protein A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D009281:Naphthalenes; D051716:Replication Protein A; D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse