Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235
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Abstract
Small molecule inhibitors of HER2 are clinically active in women with advanced HER2-positive breast cancer who have progressed on trastuzumab treatment. However, the effectiveness of this class of agents is limited by either primary resistance or acquired resistance. Using an unbiased genetic approach, we performed a genome wide loss-of-function short hairpin RNA screen to identify novel modulators of resistance to lapatinib, a recently approved anti-HER2 tyrosine kinase inhibitor. Here, we have identified the tumor suppressor PTEN as a modulator of lapatinib sensitivity in vitro and in vivo. In addition, we show that two dominant activating mutations in PIK3CA (E545K and H1047R), which are prevalent in breast cancer, also confer resistance to lapatinib. Furthermore, we show that phosphatidylinositol 3-kinase (PI3K)-induced lapatinib resistance can be abrogated through the use of NVP-BEZ235, a dual inhibitor of PI3K/mTOR. Our data show that deregulation of the PI3K pathway, either through loss-of-function mutations in PTEN or dominant activating mutations in PIK3CA, leads to lapatinib resistance, which can be effectively reversed by NVP-BEZ235.
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Constitutive 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 Eichhorn et al., 2008
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Flagged first, then by citations
Research works printed but not linked: 2
- [37]Carracedo A Ma L Teruya-Feldstein J A novel feedback loop leads toa ctivation of MAPK pathway by mTORC1 inhibitors JCI 2008 In Press PMC2518073 18725988
- [38]Maira S Stauffer F Brueggen J Identification and chracterization of NVP-BEZ235 a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity Mol Cancer Ther 2008 7 7 1851 63 18606717
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- Authors
- Eichhorn, P. J. A., Gili, M., Scaltriti, M., Serra, V., Guzman, M., Nijkamp, W., Beijersbergen, R. L., Valero, V., Seoane, J., Bernards, R., & Baselga, J.
- Affiliations
- Vall d'Hebron Institute of Oncology (ES)
- 1Medical Oncology Program, Vall d Hebron Institut de Oncologia, Barcelona, Spain;
- The Netherlands Cancer Institute (NL)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- 2Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands;
- Universitat Autònoma de Barcelona (ES)
- ORCID
- Venue
- Cancer Research
- Published
- 2008-11-14
- Volume
- 68
- Issue
- 22
- Pages
- 9221-9230
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2587064
- OpenAlex
- W2161422104
- Cited by
- 499
- References
- 44
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 23 · 2022: 7 · 2021: 16 · 2020: 13 · 2019: 22 · 2018: 23 · 2017: 28 · 2016: 23 · 2015: 44 · 2014: 46 · 2013: 57 · 2012: 50
- FWCI
- 17.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Genentech
- National Cancer Institute (U54CA112970)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- lapatinib resistance, HER2-positive breast cancer, PTEN, PIK3CA mutation, NVP-BEZ235, PI3K/mTOR dual inhibitor, HER2 tyrosine kinase inhibitor, acquired drug resistance, trastuzumab
- MeSH terms
- Trastuzumab, Lapatinib, Phosphoinositide-3 Kinase Inhibitors, Animals, Antibodies, Monoclonal, Carrier Proteins, Drug Resistance, Female, Humans, Imidazoles, Mice, Inbred BALB C, Mutation, Phosphorylation, Quinazolines, Quinolines, Signal Transduction, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositol 3-Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Mice, TOR Serine-Threonine Kinases, Antibodies, Monoclonal, Humanized
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