PT  - JOURNAL ARTICLE
AU  - Xiao, Zhan
AU  - Carrasco, Rosa A.
AU  - Schifferli, Kevin
AU  - Kinneer, Krista
AU  - Tammali, Ravinder
AU  - Chen, Hong
AU  - Rothstein, Ray
AU  - Wetzel, Leslie
AU  - Yang, Chunning
AU  - Chowdhury, Partha
AU  - Tsui, Ping
AU  - Steiner, Philipp
AU  - Jallal, Bahija
AU  - Herbst, Ronald
AU  - Hollingsworth, Robert E.
AU  - Tice, David A.
TI  - A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of <em>PTEN</em> Status on Tumor Response
AID  - 10.1158/1535-7163.MCT-15-0555
DP  - 2016 Apr 01
TA  - Molecular Cancer Therapeutics
PG  - 689--701
VI  - 15
IP  - 4
4099  - http://mct.aacrjournals.org/content/15/4/689.short
4100  - http://mct.aacrjournals.org/content/15/4/689.full
SO  - Mol Cancer Ther2016 Apr 01; 15
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.