The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3
Open accessAbstract
Oncogenic tyrosine kinases have proved to be promising targets for the development of highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (HER) family show only limited activity against HER2-driven breast cancers, despite effective inhibition of epidermal growth factor receptor (EGFR) and HER2 in vivo. The reasons for this are unclear. Signalling in trans is a key feature of this multimember family and the critically important phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 (refs 9, 10). Here we show that HER3 and consequently PI(3)K/Akt signalling evade inhibition by current HER-family TKIs in vitro and in tumours in vivo. This is due to a compensatory shift in the HER3 phosphorylation–dephosphorylation equilibrium, driven by increased membrane HER3 expression driving the phosphorylation reaction and by reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt-mediated negative-feedback signalling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abrogation of HER3 resistance by small interfering RNA knockdown restores potent pro-apoptotic activity to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumours and the therapeutic promise of this oncoprotein target. However, because HER3 signalling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to silence oncogenic HER2 signalling effectively. The biologic marker with which to assess the efficacy of HER TKIs should be the transphosphorylation of HER3 rather than autophosphorylation.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., & McGuire, W. L. (1987) · Science · doi:10.1126/science.3798106 · Cited by 11,760
The protein kinase complement of the human genome
Manning, G., Whyte, D. B., Martinez, R., Hunter, T., & Sudarsanam, S. (2002) · Science · doi:10.1126/science.1075762 · Cited by 8,145
Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia
Kantarjian, H., Sawyers, C., Hochhaus, A., Guilhot, F., Schiffer, C., Gambacorti-Passerini, C., Niederwieser, D., Resta, D., Capdeville, R., Zoellner, U., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa011573 · Cited by 2,019
Muller, W. J., Sinn, E., Pattengale, P. K., Wallace, R., & Leder, P. (1988) · Cell · doi:10.1016/0092-8674(88)90184-5 · Cited by 1,165
Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo
Meng, T.-C., Fukada, T., & Tonks, N. K. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00445-8 · Cited by 1,040
Redox Redux: Revisiting PTPs and the Control of Cell Signaling
Tonks, N. K. (2005) · Cell · doi:10.1016/j.cell.2005.05.016 · Cited by 702
Moulder, S. L., Yakes, F. M., Muthuswamy, S. K., Bianco, R., Simpson, J. F., & Arteaga, C. L. (2001) · PubMed · Cited by 548
ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor.
Soltoff, S. P., Carraway, K. L., Prigent, S. A., Gullick, W. G., & Cantley, L. C. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.6.3550 · Cited by 515
Moasser, M. M., Basso, A., Averbuch, S. D., & Rosen, N. X. (2001) · PubMed · Cited by 509
Self-citationEpidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib
Haas-Kogan, D. A., Prados, M. D., Tihan, T., Eberhard, D. A., Jelluma, N., Arvold, N. D., Baumber, R., Lamborn, K. R., Kapadia, A., Malec, M., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji161 · Cited by 465
Cited by
Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681
MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496
Berns, K., Horlings, H. M., Hennessy, B. T., Madiredjo, M., Hijmans, E. M., Beelen, K., Linn, S. C., Gonzalez-Angulo, A. M., Stemke-Hale, K., Hauptmann, M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.030 · Cited by 1,627
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
Combinatorial drug therapy for cancer in the post-genomic era
Al-Lazikani, B., Banerji, U., & Workman, P. (2012) · Nature Biotechnology · doi:10.1038/nbt.2284 · Cited by 1,070
Metadata
- Authors
- Sergina, N. V., Rausch, M., Wang, D., Blair, J., Hann, B., Shokat, K. M., & Moasser, M. M.
- Venue
- Nature
- Published
- 2007-01
- Volume
- 445
- Issue
- 7126
- Pages
- 437-441
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2017081079
- Cited by
- 991
- References
- 27
- FWCI
- 33.65
- Type
- journal article
- Language
- en
- Open access
- green
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
How to cite
Cite CoChat for the checks on this page, and the paper for its own findings.
- This page
- CoChat. (2026). Citation check: Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. https://app.cochat.ai/papers/10.1038/nature05474
- The paper
- Sergina, N. V., Rausch, M., Wang, D., Blair, J., Hann, B., Shokat, K. M., & Moasser, M. M. (2007). Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. https://doi.org/10.1038/nature05474
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
