title: Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110α inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers.
abstract: 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.
authors.affiliation: Authors' Affiliations: Departments of Medicine and Cancer Biology; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center; Vanderbilt University, Nashville, Tennessee; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts; Integrated Oncology/LabCorp; and Monogram Biosciences/LabCorp, South San Francisco, California.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Garrett
authors.forename: Cammie R
authors.initials: CR
authors.lastname: Sutton
authors.forename: Richard
authors.initials: R
authors.lastname: Kurupi
authors.forename: Carl Uli
authors.initials: CU
authors.lastname: Bialucha
authors.forename: Seth A
authors.initials: SA
authors.lastname: Ettenberg
authors.forename: Scott D
authors.initials: SD
authors.lastname: Collins
authors.forename: Qing
authors.initials: Q
authors.lastname: Sheng
authors.forename: Jerry
authors.initials: J
authors.lastname: Wallweber
authors.forename: Lisa
authors.initials: L
authors.lastname: Defazio-Eli
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D000077341:Lapatinib; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D015996:Survival Rate; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D000077341:Lapatinib; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse
references.citation: Genes Dev. 2012 Jul 15;26(14):1573-86
references.pmid: 22802530
references.citation: PLoS One. 2011 Jan 28;6(1):e16443
references.pmid: 21297994
references.citation: Mol Cancer Ther. 2012 Feb;11(2):317-28
references.pmid: 22188813
references.citation: Clin Cancer Res. 2013 Feb 1;19(3):610-9
references.pmid: 23224399
references.citation: Cancer Res. 2010 Mar 15;70(6):2485-94
references.pmid: 20215504
references.citation: Cancer Res. 2013 Feb 1;73(3):1190-200
references.pmid: 23204226
references.citation: Cancer Cell. 2009 May 5;15(5):429-40
references.pmid: 19411071
references.citation: Mol Cell Biol. 1998 Apr;18(4):2344-59
references.pmid: 9528804
references.citation: Cancer Res. 2011 Jun 1;71(11):3941-51
references.pmid: 21482676
references.citation: Stem Cells. 1998;16(6):413-28
references.pmid: 9831867
references.citation: Br J Cancer. 1998 Nov;78(10):1385-90
references.pmid: 9823984
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5021-6
references.pmid: 21385943
references.citation: Cancer. 2005 May 1;103(9):1770-7
references.pmid: 15770691
references.citation: Cancer Res. 2008 Nov 15;68(22):9221-30
references.pmid: 19010894
references.citation: EMBO J. 1999 Apr 15;18(8):2149-64
references.pmid: 10205169
references.citation: Cancer Cell. 2011 Jan 18;19(1):58-71
references.pmid: 21215704
references.citation: Breast Cancer Res Treat. 2011 Jul;128(2):447-56
references.pmid: 21594665
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):177-84
references.pmid: 19208461
references.citation: Nature. 2012 Mar 28;483(7391):603-7
references.pmid: 22460905
references.citation: Science. 1987 Jan 9;235(4785):177-82
references.pmid: 3798106
references.citation: Oncogene. 2010 Sep 16;29(37):5193-203
references.pmid: 20581867
references.citation: BMC Cancer. 2011 Jun 15;11:248
references.pmid: 21676217
references.citation: Cancer Res. 2012 May 15;72(10):2672-82
references.pmid: 22461506
references.citation: Am J Pathol. 2010 Oct;177(4):1647-56
references.pmid: 20813970
references.citation: Annu Rev Biochem. 1998;67:481-507
references.pmid: 9759495
references.citation: Cancer Res. 2008 Jul 15;68(14):5878-87
references.pmid: 18632642
references.citation: Cancer Cell. 2007 Oct;12(4):395-402
references.pmid: 17936563
references.citation: Cancer Res. 2002 Jul 15;62(14):4132-41
references.pmid: 12124352
references.citation: Methods. 2003 Jul;30(3):256-68
references.pmid: 12798140
references.citation: Clin Cancer Res. 2009 Jun 15;15(12):4147-56
references.pmid: 19509167
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22299-304
references.pmid: 20007781
references.citation: Clin Cancer Res. 2007 Aug 15;13(16):4909-19
references.pmid: 17699871
references.citation: Nature. 2012 Oct 4;490(7418):61-70
references.pmid: 23000897
references.citation: Diagn Mol Pathol. 2009 Mar;18(1):11-21
references.pmid: 19214113
references.citation: Oncogene. 2011 Jun 2;30(22):2547-57
references.pmid: 21278786
references.citation: Cancer Cell. 2007 Aug;12(2):104-7
references.pmid: 17692802
references.citation: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2718-23
references.pmid: 21368164
references.citation: Science. 1991 Oct 11;254(5029):274-7
references.pmid: 1833819