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

摘要

We examined the effects of LJM716, a 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 to 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 three 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 three weeks of treatment. Thirty weeks after treatment discontinuation, 14% of mice 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 a 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.