RT Journal Article SR Electronic T1 A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 689 OP 701 DO 10.1158/1535-7163.MCT-15-0555 VO 15 IS 4 A1 Xiao, Zhan A1 Carrasco, Rosa A. A1 Schifferli, Kevin A1 Kinneer, Krista A1 Tammali, Ravinder A1 Chen, Hong A1 Rothstein, Ray A1 Wetzel, Leslie A1 Yang, Chunning A1 Chowdhury, Partha A1 Tsui, Ping A1 Steiner, Philipp A1 Jallal, Bahija A1 Herbst, Ronald A1 Hollingsworth, Robert E. A1 Tice, David A. YR 2016 UL http://mct.aacrjournals.org/content/15/4/689.abstract AB 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.