title: A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response.
abstract: HER3/ERBB3 is a kinase-deficient member of the EGFR family receptor tyrosine kinases (RTK) that is broadly expressed and activated in human cancers. HER3 is a compelling cancer target due to its important role in activation of the oncogenic PI3K/AKT pathway. It has also been demonstrated to confer tumor resistance to a variety of cancer therapies, especially targeted drugs against EGFR and HER2. HER3 can be activated by its ligand (heregulin/HRG), which induces HER3 heterodimerization with EGFR, HER2, or other RTKs. Alternatively, HER3 can be activated in a ligand-independent manner through heterodimerization with HER2 in HER2-amplified cells. We developed a fully human mAb against HER3 (KTN3379) that efficiently suppressed HER3 activity in both ligand-dependent and independent settings. Correspondingly, KTN3379 inhibited tumor growth in divergent tumor models driven by either ligand-dependent or independent mechanisms in vitro and in vivo Most intriguingly, while investigating the mechanistic underpinnings of tumor response to KTN3379, we discovered an interesting dichotomy in that PTEN loss, a frequently occurring oncogenic lesion in a broad range of cancer types, substantially blunted the tumor response in HER2-amplified cancer, but not in the ligand-driven cancer. To our knowledge, this represents the first study ascertaining the impact of PTEN loss on the antitumor efficacy of a HER3 mAb. KTN3379 is currently undergoing a phase Ib clinical trial in patients with advanced solid tumors. Our current study may help us optimize patient selection schemes for KTN3379 to maximize its clinical benefits. Mol Cancer Ther; 15(4); 689-701. ©2016 AACR.
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD. xiaoz@medimmune.com.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Carrasco
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Kevin
authors.initials: K
authors.lastname: Schifferli
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Krista
authors.initials: K
authors.lastname: Kinneer
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Tammali
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Ray
authors.initials: R
authors.lastname: Rothstein
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Leslie
authors.initials: L
authors.lastname: Wetzel
authors.affiliation: Antibody Development and Protein Engineering, MedImmune, Inc., Gaithersburg, Maryland.
authors.forename: Chunning
authors.initials: C
authors.lastname: Yang
authors.affiliation: Antibody Development and Protein Engineering, MedImmune, Inc., Gaithersburg, Maryland.
authors.forename: Partha
authors.initials: P
authors.lastname: Chowdhury
authors.affiliation: Antibody Development and Protein Engineering, MedImmune, Inc., Gaithersburg, Maryland.
authors.forename: Ping
authors.initials: P
authors.lastname: Tsui
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Philipp
authors.initials: P
authors.lastname: Steiner
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hollingsworth
authors.affiliation: Oncology Research, MedImmune, Inc., One MedImmune Way, Gaithersburg, MD.
authors.forename: David A
authors.initials: DA
authors.lastname: Tice
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D055503:Protein Multimerization / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008024:Ligands; D051059:PTEN Phosphohydrolase; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3