The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer
Open accessAbstract
There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation.
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Cites
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“Aberrant activation of the PI3K pathway also results in resistance to antiHER2 and other anti-cancer agents (Clark et al., 2002; Nagata et al., 2004; Berns et al., 2007; Eichhorn et al., 2008).”
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Self-citationAKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity
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Cited by
PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Glaviano, A., Foo, A. S. C., Lam, H. Y., Yap, K. C. H., Jacot, W., Jones, R. H., Eng, H., Nair, M. G., Makvandi, P., Geoerger, B., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01827-6 · Cited by 2,138
Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways
Wee, P., & Wang, Z. (2017) · Cancers · doi:10.3390/cancers9050052 · Cited by 2,027
Patient-Derived Xenograft Models: An Emerging Platform for Translational Cancer Research
Hidalgo, M., Amant, F., Biankin, A. V., Budinská, E., Byrne, A. T., Caldas, C., Clarke, R. B., de Jong, S., Jonkers, J., Mælandsmo, G. M., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0001 · Cited by 1,742
Targeting PI3K in cancer: mechanisms and advances in clinical trials
Yang, J., Nie, J., Ma, X., Wei, Y., Peng, Y., & Wei, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-0954-x · Cited by 1,520
Targeted drug delivery strategies for precision medicines
Manzari, M. T., Shamay, Y., Kiguchi, H., Rosen, N., Scaltriti, M., & Heller, D. A. (2021) · Nature Reviews Materials · doi:10.1038/s41578-020-00269-6 · Cited by 1,183
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Metadata
- Authors
- Serra, V, Scaltriti, M., Prudkin, L., Eichhorn, P. J. A., Ibrahim, Y. H., Chandarlapaty, S., Markman, B., Rodriguez, O., Guzman, M., Rodriguez, S., Gili, M., Russillo, M., Parra, J. L., Singh, S., Arribas, J., Rosen, N., & Baselga, J.
- Venue
- Oncogene
- Published
- 2011-01-31
- Volume
- 30
- Issue
- 22
- Pages
- 2547-2557
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2015512041
- Cited by
- 528
- References
- 9
- FWCI
- 19.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Serra, V, Scaltriti, M., Prudkin, L., Eichhorn, P. J. A., Ibrahim, Y. H., Chandarlapaty, S., Markman, B., Rodriguez, O., Guzman, M., Rodriguez, S., Gili, M., Russillo, M., Parra, J. L., Singh, S., Arribas, J., Rosen, N., & Baselga, J. (2011). PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. https://doi.org/10.1038/onc.2010.626
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