title: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations.
abstract: Phosphatidylinositol-3-kinase (PI3K) pathway deregulation is a common event in human cancer, either through inactivation of the tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 or activating mutations of p110-alpha. These hotspot mutations result in oncogenic activity of the enzyme and contribute to therapeutic resistance to the anti-HER2 antibody trastuzumab. The PI3K pathway is, therefore, an attractive target for cancer therapy. We have studied NVP-BEZ235, a dual inhibitor of the PI3K and the downstream mammalian target of rapamycin (mTOR). NVP-BEZ235 inhibited the activation of the downstream effectors Akt, S6 ribosomal protein, and 4EBP1 in breast cancer cells. The antiproliferative activity of NVP-BEZ235 was superior to the allosteric selective mTOR complex inhibitor everolimus in a panel of 21 cancer cell lines of different origin and mutation status. The described Akt activation due to mTOR inhibition was prevented by higher doses of NVP-BEZ235. NVP-BEZ235 reversed the hyperactivation of the PI3K/mTOR pathway caused by the oncogenic mutations of p110-alpha, E545K, and H1047R, and inhibited the proliferation of HER2-amplified BT474 cells exogenously expressing these mutations that render them resistant to trastuzumab. In trastuzumab-resistant BT474 H1047R breast cancer xenografts, NVP-BEZ235 inhibited PI3K signaling and had potent antitumor activity. In treated animals, there was complete inhibition of PI3K signaling in the skin at pharmacologically active doses, suggesting that skin may serve as surrogate tissue for pharmacodynamic studies. In summary, NVP-BEZ235 inhibits the PI3K/mTOR axis and results in antiproliferative and antitumoral activity in cancer cells with both wild-type and mutated p110-alpha.
authors.affiliation: Laboratory of Oncology Research, Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.forename: Ben
authors.initials: B
authors.lastname: Markman
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.forename: Pieter J A
authors.initials: PJ
authors.lastname: Eichhorn
authors.forename: Vanesa
authors.initials: V
authors.lastname: Valero
authors.forename: Marta
authors.initials: M
authors.lastname: Guzman
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Botero
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Llonch
authors.forename: Francesco
authors.initials: F
authors.lastname: Atzori
authors.forename: Serena
authors.initials: S
authors.lastname: Di Cosimo
authors.forename: Michel
authors.initials: M
authors.lastname: Maira
authors.forename: Carlos
authors.initials: C
authors.lastname: Garcia-Echeverria
authors.forename: Josep Lluis
authors.initials: JL
authors.lastname: Parra
authors.forename: Joaquin
authors.initials: J
authors.lastname: Arribas
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C531198:dactolisib