title: Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations.
abstract: A prominent role in the pathogenesis of squamous cell carcinoma of the lung (SQCLC) has been attributed to the aberrant activation of the PI3K signaling pathway, due to amplification or mutations of the p110α subunit of class I phosphatidylinositol 3-kinase (PIK3CA) gene. The aim of our study was to determine whether different genetic alterations of PIK3CA affect the biologic properties of SQCLC and to evaluate the response to specific targeting agents in vitro and in vivo. The effects of NVP-BEZ235, NVP-BKM120, and NVP-BYL719 on two-dimensional/three-dimensional (2D/3D) cellular growth, epithelial-to-mesenchymal transition, and invasiveness were evaluated in E545K or H1047R PIK3CA-mutated SQCLC cells and in newly generated clones carrying PIK3CA alterations, as well as in a xenograft model. PIK3CA mutated/amplified cells showed increased growth rate and enhanced migration and invasiveness, associated with an increased activity of RhoA family proteins and the acquisition of a mesenchymal phenotype. PI3K inhibitors reverted this aggressive phenotype by reducing metalloproteinase production, RhoA activity, and the expression of mesenchymal markers, with the specific PI3K inhibitors NVP-BKM120 and NVP-BYL719 being more effective than the dual PI3K/mTOR inhibitor NVP-BEZ235. A xenograft model of SQCLC confirmed that PIK3CA mutation promotes the acquisition of a mesenchymal phenotype in vivo and proved the efficacy of its specific targeting drug NVP-BYL719 in reducing the growth and the expression of mesenchymal markers in xenotransplanted tumors. These data indicate that PIK3CA mutation/amplification may represent a good predictive feature for the clinical application of specific PI3K inhibitors in SQCLC patients.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. mara.bonelli@unipr.it roberta.alfieri@unipr.it.
authors.forename: Mara A
authors.initials: MA
authors.lastname: Bonelli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavazzoni
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Saccani
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. mara.bonelli@unipr.it roberta.alfieri@unipr.it.
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Quaini
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: La Monica
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy. Italian Workers' Compensation Authority (INAIL) Research Center at the University of Parma, Parma, Italy.
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cretella
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Caffarra
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Madeddu
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Frati
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, University of Parma, Parma, Italy.
authors.forename: Costanza Annamaria
authors.initials: CA
authors.lastname: Lagrasta
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Falco
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Rossetti
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fumarola
authors.affiliation: Division of Medical Oncology, University Hospital of Parma, Parma, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
authors.affiliation: Division of Medical Oncology, University Hospital of Parma, Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D058534:Class I Phosphatidylinositol 3-Kinases; D007093:Imidazoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D013844:Thiazoles; C571178:NVP-BKM120; C585539:Alpelisib; C484760:PIK3CA protein, human; C531198:dactolisib