NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations

Serra, Violeta; Markman, Benjamin; Scaltriti, Maurizio; Eichhorn, Pieter J.A.; Valero, Vanesa; Guzmán, Marta; Botero, María L.; Llonch, Elisabeth; Atzori, Francesco; Cosimo, Serena Di; Maira, Michel; García‐Echeverría, Carlos; Parra, Josep Lluis; Arribas, Joaquı́n; Baselga, José

doi:10.1158/0008-5472.can-08-1385

Cited by 696 publications

(585 citation statements)

References 29 publications

Supporting

Mentioning

525

Contrasting

Unclassified

Order By: Relevance

“…This later results suggest that vascular permeability reduction, which can be monitored noninvasively by dynamic contrast-enhanced magnetic resonance imaging might be a useful pharmacodynamic measure in clinical trials and might serve as an early response biomarker predictive of longer-term efficacy. In preclinical in vivo models (Engelman et al, 2008;Serra et al, 2008;Maira et al, 2008a), NVP-BEZ235 was well tolerated at the efficacious doses when compared with vehicle-treated animals, with no significant difference seen in the body weight. Unlike other modulators of the PI3K/Akt pathway, no statistically significant changes in blood glucose levels were observed in the animals treated with NVP-BEZ235 after in vivo efficacy experiments in mice or rats.…”

Section: Inhibitors Of the Lipid Kinase Activity Of Pi3kmentioning

confidence: 96%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

View full text Add to dashboard Cite

Section: Inhibitors Of the Lipid Kinase Activity Of Pi3kmentioning

confidence: 96%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

View full text Add to dashboard Cite

“…Xenografts samples were prepared as described earlier (Serra et al, 2008). Primary antibody was anti-HER2 (CB11, Biogenex) and secondary antibody was from Amersham.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

et al. 2008

View full text Add to dashboard Cite

Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially nonoverlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo-(HER2/HER2) and hetero-(HER2/EGFR and HER2/HER3) dimers. Lapatinibinduced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

show abstract

“…BEZ235 inhibits PI3K, mTORC1, and mTORC2. [98] Early data demonstrate it is well tolerated. Nausea, diarrhea, and vomiting are the only common toxicities, and the doselimiting toxicities are fatigue and thrombocytopenia.…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

View full text Add to dashboard Cite

The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

show abstract

NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations

Cited by 696 publications

References 29 publications

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Contact Info

Product

Resources

About