title: Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors.
abstract: Non-small-cell lung cancer (NSCLC) is a common malignancy with a poor prognosis. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor-suppressor loss. Smad4 is an established tumor suppressor in pancreatic and colon cancer; however, the consequences of Smad4 loss in lung cancer are largely unknown. We evaluated Smad4 expression in human NSCLC samples and examined Smad4 alterations in large NSCLC data sets and found that reduced Smad4 expression is common in human NSCLC and occurs through a variety of mechanisms, including mutation, homozygous deletion and heterozygous loss. We modeled Smad4 loss in lung cancer by deleting Smad4 in airway epithelial cells and found that Smad4 deletion both initiates and promotes lung tumor development. Interestingly, both Smad4(-/-) mouse tumors and human NSCLC samples with reduced Smad4 expression demonstrated increased DNA damage, whereas Smad4 knockdown in lung cancer cells reduced DNA repair and increased apoptosis after DNA damage. In addition, Smad4-deficient NSCLC cells demonstrated increased sensitivity to both chemotherapeutics that inhibit DNA topoisomerase and drugs that block double-strand DNA break repair by non-homologous end joining. In sum, these studies establish Smad4 as a lung tumor suppressor and suggest that the defective DNA repair phenotype of Smad4-deficient tumors can be exploited by specific therapeutic strategies.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Haeger
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Thompson
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.
authors.forename: Sean
authors.initials: S
authors.lastname: Kalra
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Cleaver
authors.affiliation: Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.
authors.forename: Daniel
authors.initials: D
authors.lastname: Merrick
authors.affiliation: Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.|Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Malkoski
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004260:DNA Repair; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051901:Smad4 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D059003:Topoisomerase Inhibitors