Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase

Joan T. Garrett, María Graciela Olivares, Cammie Rinehart, Nara D. Granja-Ingram, Violeta Sánchez, Anindita Chakrabarty, Bhuvanesh Dave, Rebecca S. Cook, William Pao, Eliot McKinely, H. C. Manning, Jenny Chang, Carlos L. Arteaga

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Abstract

Sustained and complete inhibition of HER3 and its output to PI3K/Akt are required for the optimal antitumor effect of therapeutic inhibitors of the HER2 oncogene. Here, we show that, after inhibition of the HER2 tyrosine kinase with lapatinib, there is PI3K/Akt and FoxO3a-dependent up-regulation of HER3 mRNA and protein. Up-regulated HER3 was then phosphorylated by residual HER2 activity, thus partially maintaining P-Akt and limiting the antitumor action of lapatinib. Inhibition of HER3 with siRNA or a neutralizing HER3 antibody sensitized HER2+ breast cancer cells and xenografts to lapatinib both in vitro and in vivo. Combined blockade of HER2 and HER3 inhibited pharmacodynamic biomarkers of PI3K/Akt activity more effectively than each inhibitor alone. These results suggest that because of HER3-mediated compensation, current clinical inhibitors of HER2 and PI3K/Akt will not block the PI3K pathway completely. They also suggest that therapeutic inhibitors of HER3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with HER2- and PI3K-dependent cancers.

Original languageEnglish (US)
Pages (from-to)5021-5026
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number12
DOIs
StatePublished - Mar 22 2011

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Phosphatidylinositol 3-Kinases
Protein-Tyrosine Kinases
Up-Regulation
Therapeutic Uses
Neutralizing Antibodies
Oncogenes
Heterografts
Small Interfering RNA
Biomarkers
Breast Neoplasms
Messenger RNA
lapatinib
Neoplasms
Proteins

ASJC Scopus subject areas

  • General

Cite this

Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. / Garrett, Joan T.; Olivares, María Graciela; Rinehart, Cammie; Granja-Ingram, Nara D.; Sánchez, Violeta; Chakrabarty, Anindita; Dave, Bhuvanesh; Cook, Rebecca S.; Pao, William; McKinely, Eliot; Manning, H. C.; Chang, Jenny; Arteaga, Carlos L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 12, 22.03.2011, p. 5021-5026.

Research output: Contribution to journalArticle

Garrett, JT, Olivares, MG, Rinehart, C, Granja-Ingram, ND, Sánchez, V, Chakrabarty, A, Dave, B, Cook, RS, Pao, W, McKinely, E, Manning, HC, Chang, J & Arteaga, CL 2011, 'Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 12, pp. 5021-5026. https://doi.org/10.1073/pnas.1016140108
Garrett, Joan T. ; Olivares, María Graciela ; Rinehart, Cammie ; Granja-Ingram, Nara D. ; Sánchez, Violeta ; Chakrabarty, Anindita ; Dave, Bhuvanesh ; Cook, Rebecca S. ; Pao, William ; McKinely, Eliot ; Manning, H. C. ; Chang, Jenny ; Arteaga, Carlos L. / Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 12. pp. 5021-5026.
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