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 communityidentifying 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.
| Original language | English |
|---|---|
| Pages (from-to) | 58743-58758 |
| Number of pages | 16 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 37 |
| DOIs | |
| Publication status | Published - 2016 |
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Keywords
- Drugs network
- FDA-approved drugs
- Gene expression signatures
- Oncogenes
- PI3K-dependent pathways
ASJC Scopus subject areas
- Oncology
Cite this
Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDAapproved compounds. / Carrella, Diego; Manni, Isabella; Tumaini, Barbara; Dattilo, Rosanna; Papaccio, Federica; Mutarelli, Margherita; Sirci, Francesco; Amoreo, Carla A.; Mottolese, Marcella; Iezzi, Manuela; Ciolli, Laura; Aria, Valentina; Bosotti, Roberta; Isacchi, Antonella; Loreni, Fabrizio; Bardelli, Alberto; Avvedimento, Vittorio E.; di Bernardo, Diego; Cardone, Luca.
In: Oncotarget, Vol. 7, No. 37, 2016, p. 58743-58758.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Computational drugs repositioning identifies inhibitors of oncogenic PI3K/AKT/P70S6K-dependent pathways among FDAapproved compounds
AU - Carrella, Diego
AU - Manni, Isabella
AU - Tumaini, Barbara
AU - Dattilo, Rosanna
AU - Papaccio, Federica
AU - Mutarelli, Margherita
AU - Sirci, Francesco
AU - Amoreo, Carla A.
AU - Mottolese, Marcella
AU - Iezzi, Manuela
AU - Ciolli, Laura
AU - Aria, Valentina
AU - Bosotti, Roberta
AU - Isacchi, Antonella
AU - Loreni, Fabrizio
AU - Bardelli, Alberto
AU - Avvedimento, Vittorio E.
AU - di Bernardo, Diego
AU - Cardone, Luca
PY - 2016
Y1 - 2016
N2 - 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 communityidentifying 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.
AB - 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 communityidentifying 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.
KW - Drugs network
KW - FDA-approved drugs
KW - Gene expression signatures
KW - Oncogenes
KW - PI3K-dependent pathways
UR - http://www.scopus.com/inward/record.url?scp=84991386993&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84991386993&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.11318
DO - 10.18632/oncotarget.11318
M3 - Article
AN - SCOPUS:84991386993
VL - 7
SP - 58743
EP - 58758
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 37
ER -