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15357163mct150555-sup-152147_2_supp_3341645_j213p0.pptx (785.11 kB)

Supplementary data: Figures 1-6; Tables 1 and 2 from A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response

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posted on 2023-04-03, 15:40 authored by Zhan Xiao, Rosa A. Carrasco, Kevin Schifferli, Krista Kinneer, Ravinder Tammali, Hong Chen, Ray Rothstein, Leslie Wetzel, Chunning Yang, Partha Chowdhury, Ping Tsui, Philipp Steiner, Bahija Jallal, Ronald Herbst, Robert E. Hollingsworth, David A. Tice

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

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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.

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