title: Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds.
abstract: The discovery of inhibitors for oncogenic signalling pathways remains a key focus in modern oncology, based on personalized and targeted therapeutics. Computational drug repurposing via the analysis of FDA-approved drug network is becoming a very effective approach to identify therapeutic opportunities in cancer and other human diseases. Given that gene expression signatures can be associated with specific oncogenic mutations, we tested whether a "reverse" oncogene-specific signature might assist in the computational repositioning of inhibitors of oncogenic pathways. As a proof of principle, we focused on oncogenic PI3K-dependent signalling, a molecular pathway frequently driving cancer progression as well as raising resistance to anticancer-targeted therapies. We show that implementation of "reverse" oncogenic PI3K-dependent transcriptional signatures combined with interrogation of drug networks identified inhibitors of PI3K-dependent signalling among FDA-approved compounds. This led to repositioning of Niclosamide (Niclo) and Pyrvinium Pamoate (PP), two anthelmintic drugs, as inhibitors of oncogenic PI3K-dependent signalling. Niclo inhibited phosphorylation of P70S6K, while PP inhibited phosphorylation of AKT and P70S6K, which are downstream targets of PI3K. Anthelmintics inhibited oncogenic PI3K-dependent gene expression and showed a cytostatic effect in vitro and in mouse mammary gland. Lastly, PP inhibited the growth of breast cancer cells harbouring PI3K mutations. Our data indicate that drug repositioning by network analysis of oncogene-specific transcriptional signatures is an efficient strategy for identifying oncogenic pathway inhibitors among FDA-approved compounds. We propose that PP and Niclo should be further investigated as potential therapeutics for the treatment of tumors or diseases carrying the constitutive activation of the PI3K/P70S6K signalling axis.
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Carrella
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovations, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Manni
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tumaini
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Biobank Unit, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Dattilo
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovations, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Papaccio
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Mutarelli
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sirci
authors.affiliation: S.C. Anatomia Patologica, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Amoreo
authors.affiliation: S.C. Anatomia Patologica, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.affiliation: Immuno-Oncology Laboratory, Aging Research Center, G. d'Annunzio University of Chieti, Pescara, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.affiliation: Immuno-Oncology Laboratory, Aging Research Center, G. d'Annunzio University of Chieti, Pescara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ciolli
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Aria
authors.affiliation: Nerviano Medical Sciences SRL, Nerviano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bosotti
authors.affiliation: Nerviano Medical Sciences SRL, Nerviano, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loreni
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Torino, Italy.|Department of Oncology, University of Torino, Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.
authors.forename: Vittorio E
authors.initials: VE
authors.lastname: Avvedimento
authors.affiliation: Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy.|Department of Electrical Engineering and Information Technology, University of Naples "Federico II", Naples, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: di Bernardo
authors.affiliation: Department of Research, Advanced Diagnostics, and Technological Innovations, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cardone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D019295:Computational Biology; D017277:Drug Approval; D058492:Drug Repositioning; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D009534:Niclosamide / Q000494:pharmacology / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011774:Pyrvinium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011774:Pyrvinium Compounds; C024631:pyrvinium; D009534:Niclosamide; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa
keywords: FDA-approved drugs; PI3K-dependent pathways; drugs network; gene expression signatures; oncogenes