Enhanced efficacy of AKT and FAK kinase combined inhibition in squamous cell lung carcinomas with stable reduction in PTEN
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Andrea Cavazzoni1, Silvia La Monica1, Roberta Alfieri1, Andrea Ravelli1, Nele Van Der Steen2, Rocco Sciarrillo2, Denise Madeddu1, Costanza Anna Maria Lagrasta1, Federico Quaini1, Mara Bonelli1, Claudia Fumarola1, Daniele Cretella1, Graziana Digiacomo1, Marcello Tiseo3, Godefridus J. Peters2, Andrea Ardizzoni4, Pier Giorgio Petronini1,* and Elisa Giovannetti2,5,*
1Department of Medicine and Surgery, University of Parma, Parma, Italy
2Department of Medical Oncology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
3Medical Oncology Unit, University Hospital of Parma, Parma, Italy
4Division of Medical Oncology, Sant'Orsola-Malpighi University Hospital, Bologna, Italy
5Cancer Pharmacology Lab, AIRC/Start-Up Unit, University of Pisa, Pisa, Italy
*Joint last authors
Andrea Cavazzoni, email: firstname.lastname@example.org
Roberta Alfieri, email: email@example.com
Keywords: PTEN, FAK, PI3K, target therapy, squamous lung carcinoma
Received: November 25, 2016 Accepted: May 12, 2017 Published: May 23, 2017
Squamous cell lung carcinoma (SCC) accounts for 30% of patients with NSCLC and to date, no molecular targeted agents are approved for this type of tumor. However, recent studies have revealed several oncogenic mutations in SCC patients, including an alteration of the PI3K/AKT pathway, i.e. PI3K point mutations and amplification, AKT mutations and loss or reduced PTEN expression. Prompted by our observation of a correlation between PTEN loss and FAK phosphorylation in a cohort of patients with stage IV SCC, we evaluated the relevance of PTEN loss in cancer progression as well as the efficacy of a new combined treatment with the pan PI3K inhibitor buparlisip and the FAK inhibitor defactinib. An increase in AKT and FAK phosphorylation, associated with increased proliferation and invasiveness, paralleled by the acquisition of mesenchymal markers, and overexpression of the oncomir miR-21 were observed in SKMES-1-derived cell clones with a stable reduction of PTEN. Notably, the combined treatment induced a synergistic inhibition of cell proliferation, and a significant reduction in cell migration and invasion only in cells with reduced PTEN. The molecular mechanisms underlying these findings were unraveled using a specific RTK array that showed a reduction in phosphorylation of key kinases such as JNK, GSK-3 α/β, and AMPK-α2, due to the concomitant decrease in AKT and FAK activation. In conclusion, the combination of buparlisib and defactinib was effective against cells with reduced PTEN and warrants further studies as a novel therapeutic strategy for stage IV SCC patients with loss of PTEN expression.
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