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 or GDC-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 than combining either GDC-0068 or GDC-0941 with cetuximab, an EGFR-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.
authors.affiliation: 1Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Tao
authors.forename: Pau
authors.initials: P
authors.lastname: Castel
authors.forename: Nina
authors.initials: N
authors.lastname: Radosevic-Robin
authors.forename: Moshe
authors.initials: M
authors.lastname: Elkabets
authors.forename: Neil
authors.initials: N
authors.lastname: Auricchio
authors.forename: Nicola
authors.initials: N
authors.lastname: Aceto
authors.forename: Gregory
authors.initials: G
authors.lastname: Weitsman
authors.forename: Paul
authors.initials: P
authors.lastname: Barber
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojnovic
authors.forename: Haley
authors.initials: H
authors.lastname: Ellis
authors.forename: Natasha
authors.initials: N
authors.lastname: Morse
authors.forename: Nerissa Therese
authors.initials: NT
authors.lastname: Viola-Villegas
authors.forename: Ana
authors.initials: A
authors.lastname: Bosch
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.forename: Saswati
authors.initials: S
authors.lastname: Hazra
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.forename: Phillip
authors.initials: P
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Bergamaschi
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
mesh_terms: D061067:Antibodies, Monoclonal, Humanized; D015153:Blotting, Western; D045744:Cell Line, Tumor; D000068818:Cetuximab; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D020890:Neuregulin-1 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D007074:Immunoglobulin G; D007191:Indazoles; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D020893:Receptor, ErbB-3; D013449:Sulfonamides; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C569960:MEHD7945A; C094131:NRG1 protein, human; C583616:ipatasertib; C581292:ERBB3 protein, human