Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110α inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers.

Garrett JT, Sutton CR, Kurupi R, Bialucha CU, Ettenberg SA, Collins SD, Sheng Q, Wallweber J, Defazio-Eli L, Arteaga CL
Cancer Res. 2013 73 (19): 6013-23

PMID: 23918797 · PMCID: PMC3790862 · DOI:10.1158/0008-5472.CAN-13-1191

We examined the effects of LJM716, an HER3 (ERBB3) neutralizing antibody that inhibits ligand-induced and ligand-independent HER3 dimerization, as a single agent and in combination with BYL719, an ATP competitive p110α-specific inhibitor, against HER2-overexpressing breast and gastric cancers. Treatment with LJM716 reduced HER2-HER3 and HER3-p85 dimers, P-HER3 and P-AKT, both in vitro and in vivo. Treatment with LJM716 alone markedly reduced growth of BT474 xenografts. The combination of LJM716/lapatinib/trastuzumab significantly improved survival of mice with BT474 xenografts compared with lapatinib/trastuzumab (P = 0.0012). LJM716 and BYL719 synergistically inhibited growth in a panel of HER2+ and PIK3CA mutant cell lines. The combination also inhibited P-AKT in HER2-overexpressing breast cancer cells and growth of HER2+ NCI-N87 gastric cancer xenografts more potently than LJM716 or BYL719 alone. Trastuzumab-resistant HER2+/PIK3CA mutant MDA453 xenografts regressed completely after 3 weeks of therapy with LJM716 and BYL719, whereas either single agent inhibited growth only partially. Finally, mice with BT474 xenografts treated with trastuzumab/LJM716, trastuzumab/BYL719, LJM716/BYL719, or trastuzumab/LJM716/BYL719 exhibited similar rates of tumor regression after 3 weeks of treatment. Thirty weeks after treatment discontinuation, 14% of mice were treated with trastuzumab/LJM716/BYL719, whereas >80% in all other treatment groups were sacrificed due to a recurrent large tumor burden (P = 0.0066). These data suggest that dual blockade of the HER2 signaling network with an HER3 antibody that inhibits HER2-HER3 dimers in combination with a p110α-specific inhibitor in the absence of a direct HER2 antagonist is an effective treatment approach against HER2-overexpressing cancers.

MeSH Terms (23)

Animals Antibodies, Monoclonal, Humanized Antineoplastic Agents Breast Neoplasms Cell Proliferation Class I Phosphatidylinositol 3-Kinases Female Humans Immunoblotting Immunoprecipitation Lapatinib Mice Phosphorylation Protein Multimerization Proto-Oncogene Proteins c-akt Quinazolines Receptor, ErbB-2 Receptor, ErbB-3 Signal Transduction Survival Rate Trastuzumab Tumor Cells, Cultured Xenograft Model Antitumor Assays

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