NVP-BEZ235, a Dual PI3K/mTOR Inhibitor, Prevents PI3K Signaling and Inhibits the Growth of Cancer Cells with Activating PI3K Mutations
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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-α. 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-α, 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-α. [Cancer Res 2008;68(19):8022–30]
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BEZ235 showed satisfactory antitumor activity against various cancer types in a preclinical model.
“Although BEZ235 showed satisfactory antitumor activity against various cancer types in a preclinical model, poor tolerability and high adverse events were observed in clinical trials38–41.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [39]
The “NVP-BEZ235 antitumor activity in vivo” section reports suppressed growth in a preclinical breast-cancer xenograft model. The cell-proliferation results also report inhibition across 21 cancer cell lines of different origins, but the paper does not show antitumor activity across various cancer types in animal models. (LLM, conf=0.85)
Experimental — accuracy not yet measuredBEZ235 showed poor tolerability and high adverse events in clinical trials.
“Although BEZ235 showed satisfactory antitumor activity against various cancer types in a preclinical model, poor tolerability and high adverse events were observed in clinical trials38–41.”
From Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization (2025) · cites this paper as [39]
The Discussion reports reduced tumor growth in mouse xenografts, not outcomes in clinical trials. Searches for clinical-trial tolerability, safety, and adverse events found no passage addressing the attributed claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredActivation of the lysosomal two pore channel (TPC) by nicotinic acid adenine dinucleotide phosphate (NAADP) induces autophagy, which can selectively be inhibited by the TPC blocker NED-19, or by pre-incubation with BAPTA, showing that lysosomal calcium also modulates autophagy.
“The activation of the lysosomal two pore channel (TPC), by nicotinic acid adenine dinucleotide phosphate (NAADP) induces autophagy, which can selectively be inhibited by the TPC blocker NED-19, or by pre-incubation with BAPTA, showing that lysosomal calcium also modulates autophagy.244”
From Guidelines for the use and interpretation of assays for monitoring autophagy (2012) · cites this paper as [244]
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredConstitutive activation of PI3K via overexpression of PIK3CA mutants conferred resistance to trastuzumab in laboratory studies.
“Constitutive activation of PI3K, via overexpression of PIK3CA mutants, conferred resistance to the antibody in laboratory studies (Chakrabarty et al., 2010; Eichhorn et al., 2008; Serra et al., 2008).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Serra et al., 2008
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- Authors
- Serra, V., Markman, B., Scaltriti, M., Eichhorn, P. J. A., Valero, V., Guzman, M., Botero, M. L., Llonch, E., Atzori, F., Di Cosimo, S., Maira, M., Garcia-Echeverria, C., Parra, J. L., Arribas, J., & Baselga, J.
- Affiliations
- Novartis (Switzerland) (CH)
- 1Laboratory of Oncology Research, Medical Oncology Service, and 2Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain; and 3Novartis Institutes for BioMedical Research-Novartis Oncology, Basel, Switzerland
- ORCID
- Venue
- Cancer Research
- Published
- 2008-09-30
- Volume
- 68
- Issue
- 19
- Pages
- 8022-8030
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2039628288
- Semantic Scholar
- 8fa41e8f1268f9a83ce0307012255ef8f8f14f9b
- Cited by
- 787
- References
- 34
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 10 · 2023: 30 · 2022: 14 · 2021: 36 · 2020: 43 · 2019: 24 · 2018: 36 · 2017: 34 · 2016: 44 · 2015: 58 · 2014: 79 · 2013: 76 · 2012: 90
- FWCI
- 25.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Breast Cancer Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- NVP-BEZ235, PI3K/mTOR inhibitors, PI3K signaling, trastuzumab resistance, HER2-amplified breast cancer, BT474 cells, Akt activation, ribosomal protein S6, 4E-BP1, everolimus, pharmacodynamic biomarkers, anticancer activity
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Animals, Antineoplastic Agents, Breast Neoplasms, Enzyme Activation, Female, Humans, Imidazoles, Mice, Nude, Mutation, Protein Kinases, Quinolines, Tumor Cells, Cultured, Signal Transduction, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, TOR Serine-Threonine Kinases
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