Figure 1: KTN3379 specifically binds to HER3; Figure 2: KTN3379 suppresses cell-growth in HRG-HER3 autocrine cells and HRGinduced VEGF secretion; Figure 3: KTN3379 arrests HER2+ breast cancer cells in G0/G1-phase; Figure 4: KTN3379 is inactive in HER3-positive but HRG-negative Snu16 xenograft model; Figure 5: PTEN knockdown does not impact the growth behavior of HMCB; Figure 6: Full dose response curves of KTN3379, Pertuzumab and Cetuximab in HMCB cells with or without PTEN-knockout in 6-day proliferation assay; Supplementary Table 1 Summary of Kinetic Rate Constants and Dissociation Constants for the Binding of KTN3379 to Human HER3, Cynomolgus Monkey HER3, and Murine Her3 Proteins; Supplementary Table 2 Expression and mutation status of HER3 pathway components of models used in this manuscript
ARTICLE 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.
