PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.

Abstract

Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies.

• Authors: Michele Milella, Italia Falcone, Fabiana Conciatori, Silvia Matteoni, Andrea Sacconi, Teresa De Luca, Chiara Bazzichetto, Vincenzo Corbo, Michele Simbolo, Isabella Sperduti, Antonina Benfante, Anais Del Curatolo, Ursula Cesta Incani, Federico Malusa, Adriana Eramo, Giovanni Sette, Aldo Scarpa, Marina Konopleva, Michael Andreeff, James Andrew McCubrey, Giovanni Blandino, Matilde Todaro, Giorgio Stassi, Ruggero De Maria, Francesco Cognetti, Donatella Del Bufalo, Ludovica Ciuffreda
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 43013 (02 21 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28220839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• RNA, Small Interfering
• STAT3 Transcription Factor
• STAT3 protein, human
• trametinib
• Everolimus
• MTOR protein, human
• JAK1 protein, human
• Janus Kinase 1
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• MAP Kinase Kinase Kinases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Cell Line, Tumor
• Drug Synergism
• Everolimus (pharmacology)
• Female
• Humans
• Janus Kinase 1 (genetics, metabolism)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• Mice
• Mice, Nude
• Neoplastic Stem Cells (cytology, drug effects, metabolism)
• PTEN Phosphohydrolase (antagonists & inhibitors, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pyridones (pharmacology)
• Pyrimidinones (pharmacology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)