Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer

Jessica J. Tao, Pau Castel, Nina Radosevic-Robin, Moshe Elkabets, Neil Auricchio, Nicola Aceto, Gregory Weitsman, Paul Barber, Borivoj Vojnovic, Haley Ellis, Natasha Morse, Nerissa Therese Viola-Villegas, Ana Bosch, Dejan Juric, Saswati Hazra, Sharat Singh, Phillip Kim, Anna Bergamaschi, Shyamala Maheswaran, Tony NgFrédérique Penault-Llorca, Jason S. Lewis, Lisa A. Carey, Charles M. Perou, José Baselga, Maurizio Scaltriti

Research output: Contribution to journalArticlepeer-review

Abstract

Both abundant epidermal growth factor receptor (EGFR or ErbB1) and high activity of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway are common and therapeutically targeted in triple-negative breast cancer (TNBC). However, activation of another EGFR family member [human epidermal growth factor receptor 3 (HER3) (or ErbB3)] may limit the antitumor effects of these drugs. We found that TNBC cell lines cultured with the EGFR or HER3 ligand EGF or heregulin, respectively, and treated with either an Akt inhibitor (GDC- 0068) or a PI3K inhibitor (GDC-0941) had increased abundance and phosphorylation of HER3. The phosphorylation of HER3 and EGFR in response to these treatments was reduced by the addition of a dual EGFR and HER3 inhibitor (MEHD7945A). MEHD7945A also decreased the phosphorylation (and activation) of EGFR and HER3 and the phosphorylation of downstream targets that occurred in response to the combination of EGFR ligands and PI3K-Akt pathway inhibitors. In culture, inhibition of the PI3K-Akt pathway combined with either MEHD7945A or knockdown of HER3 decreased cell proliferation compared with inhibition of the PI3K-Akt pathway alone. Combining either GDC-0068 orGDC-0941 with MEHD7945A inhibited the growth of xenografts derived from TNBC cell lines or from TNBC patient tumors, and this combination treatment was also more effective thancombining eitherGDC-0068 orGDC-0941 with cetuximab, anEGFR-targeted antibody.After therapy with EGFR-targeted antibodies, some patients had residual tumors with increased HER3 abundance and EGFR/HER3 dimerization (an activating interaction). Thus, we propose that concomitant blockade of EGFR, HER3, and the PI3K-Akt pathway in TNBC should be investigated in the clinical setting.

Original languageEnglish (US)
Article numberra29
JournalScience signaling
Volume7
Issue number318
DOIs
StatePublished - Mar 25 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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