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

Authors: Tao, J. J.; Castel, P.; Radosevic-Robin, N.; Elkabets, M.; Auricchio, N.; Aceto, N.; Weitsman, G.; Barber, P.; Vojnovic, B.; Ellis, H.; Morse, N.; Viola-Villegas, N. T.; Bosch, A.; Juric, D.; Hazra, S.; Singh, S.; Kim, P.; Bergamaschi, A.; Maheswaran, S.; Ng, T.; Penault-Llorca, F.; Lewis, J. S.; Carey, L. A.; Perou, C. M.; Baselga, J.; Scaltriti, M.
Article Title: Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer
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.
Keywords: signal transduction; protein kinase b; controlled study; protein phosphorylation; treatment response; unclassified drug; human cell; cancer combination chemotherapy; drug efficacy; monotherapy; nonhuman; antineoplastic agent; cell proliferation; animal cell; mouse; enzyme inhibition; protein protein interaction; animal experiment; animal model; in vivo study; cancer cell culture; enzyme activation; in vitro study; tumor xenograft; cetuximab; phosphatidylinositol 3 kinase; single drug dose; dimerization; gene silencing; epidermal growth factor receptor 3; concentration response; epidermal growth factor receptor kinase inhibitor; antiproliferative activity; triple negative breast cancer; comparative effectiveness; neu differentiation factor; multicenter study (topic); pictilisib; human; female; priority journal; article; ipatasertib; mehd 7945a; mehd7945a
Journal Title: Science Signaling
Volume: 7
Issue: 318
ISSN: 1945-0877
Publisher: American Association for the Advancement of Science  
Date Published: 2014-03-25
Start Page: ra29
Language: English
DOI: 10.1126/scisignal.2005125
PROVIDER: scopus
PUBMED: 24667376
PMCID: PMC4283215
Notes: Export Date: 1 May 2014 -- Source: Scopus
Citation Impact
MSK Authors
  1. Jason S Lewis
    381 Lewis
  2. Natasha Morse
    8 Morse
  3. Pau Castel
    25 Castel
  4. Jose T Baselga
    483 Baselga
  5. Maurizio Scaltriti
    167 Scaltriti
  6. Haley Lynn Ellis
    7 Ellis