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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.

SUBMITTER: Carrella D

PROVIDER: S-EPMC5312272 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds.

Carrella Diego D Manni Isabella I Tumaini Barbara B Dattilo Rosanna R Papaccio Federica F Mutarelli Margherita M Sirci Francesco F Amoreo Carla A CA Mottolese Marcella M Iezzi Manuela M Ciolli Laura L Aria Valentina V Bosotti Roberta R Isacchi Antonella A Loreni Fabrizio F Bardelli Alberto A Avvedimento Vittorio E VE di Bernardo Diego D Cardone Luca L

Oncotarget 20160901 37

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 assis ...[more]

PMID: 27542212

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Project description:The inability of the adult human heart to regenerate lost or damaged myocardial tissue has created one of the most pressing public health dilemmas due to the devastating impact of heart failure. Our group and others have outlined several regulators of cardiomyocyte mitosis that may impact the regenerative capacity of the adult myocardium in mammals. Recently, we reported that the transcription factors Meis1 and Hoxb13 regulate postnatal cardiomyocyte cell cycle arrest, where concomitant deletion of both genes induced cardiomyocyte proliferation and myocardial regeneration following ischemic injury. These studies suggest that pharmacological targeting Meis1 and Hoxb13 transcriptional activity could be a viable path towards heart regeneration. Therefore, we performed an in-silico screen to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the published crystal structure of Meis1 and Hoxb13 bound to DNA. Our screen yielded several candidates based on binding profiles to either Meis1 DNA binding domain, Hoxb13 DNA binding domain, or the interface between Meis1 and Hoxb13, as well as safety and side effect profiles. Out of the shortlist of top hits, paromomycin and neomycin induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay, and disruption of DNA binding by EMSA. X-ray crystal structure revealed that both paromomycin and neomycin bind to Meis1 near the Hoxb13 interaction site where they interact with 3 out of the 5 Meis1 amino acids that participate in DNA-binding. The crystal structure also demonstrates that both drugs bind at the interface of Meis1 homodimer, therefore placing one of the Meis1 monomers in a position incompatible with DNA-binding. Importantly, administration of paromomycin-neomycin combination by intraperitoneal injection in mice induced cardiomyocyte proliferation, improved left ventricular (LV) systolic function and decreased scar formation in two models of ischemic reperfusion injury in mice. Finally, dual intravenous administration of the paromomycin-neomycin combination in Yorkshire pigs following cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved LV systolic function, and decreased scar formation. Collectively, we identified paromomycin and neomycin as FDA-approved drugs with therapeutic potential for induction of heart regeneration in humans.

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Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds.

Publications

Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDA-approved compounds.

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