title: Genetic mutation of p53 and suppression of the miR-17∼92 cluster are synthetic lethal in non-small cell lung cancer due to upregulation of vitamin D Signaling.
abstract: Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We used a library of oligonucleotide inhibitors of microRNAs, a class of posttranscriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in non-small cell lung cancer (NSCLC). Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific downregulation of the miR-17∼92 polycistron, and this downregulation was toxic only in the context of p53 loss. Mechanistic studies indicated that the selective toxicity of miR-17∼92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1, a rate-limiting enzyme in the 1α,25-dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach used in this study can identify clinically relevant synthetic lethal interactions and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients.
authors.affiliation: Division of Basic Sciences, Southwestern Graduate School of Biomedical Sciences, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: Robert
authors.initials: R
authors.lastname: Borkowski
authors.affiliation: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Liqin
authors.initials: L
authors.lastname: Du
authors.affiliation: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Zhenze
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Division of Basic Sciences, Southwestern Graduate School of Biomedical Sciences, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McMillan
authors.affiliation: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Adam
authors.initials: A
authors.lastname: Kosti
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: Chin-Rang
authors.initials: CR
authors.lastname: Yang
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Milind
authors.initials: M
authors.lastname: Suraokar
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. Department of Pathology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. Department of Pharmacology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. Department of Cell Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. pertsemlidis@uthscsa.edu michael.white@utsouthwestern.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.affiliation: Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. Department of Pediatrics, The University of Texas Health Science Center at San Antonio, San Antonio, Texas. pertsemlidis@uthscsa.edu michael.white@utsouthwestern.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pertsemlidis
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009154:Mutation; D018167:Receptors, Calcitriol / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D019098:Telomerase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics; D014807:Vitamin D / Q000235:genetics* / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase / Q000096:biosynthesis
chemical_list: C552310:MIRN1226 microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D018167:Receptors, Calcitriol; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014807:Vitamin D; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D019098:Telomerase