Article Figures & Data
Figures
- Figure 1.
Schematic representation of the molecular pathways activated by CD74–NRG1. CD74–NRG1 provides the ligand for ERBB3 receptors inducing its heterodimerization with ERBB2, and subsequent activation of the PI3K–AKT and MAPK pathways, in an autocrine (cytoplasm cell 1) and juxtacrine (cytoplasm cell 2) manner, resulting in an abnormal cell proliferation. The mechanism of action is expected to be the same for SCL3A2–NRG1. In the CD74–NRG1 fusion protein, the part coming from CD74 is colored in brown and the part coming from NRG1, in pink. Kinase domains of ERBB2 and ERBB3 receptors are colored in yellow. Adaptor and enzymes are represented in orange and members of the signaling cascade, in red.
Tables
- Table 1.
Overview of ERBB3 inhibitors
Name (antibody) Target Biologic effect Clinical status MM-121 (SAR256212) ERBB3 In combination with cetuximab, it blocks reactivation of ERBB3 in mice EGFR T790M-L858R, resulting in a sustained and durable response (31, 55, 56) – Completed phase I safety and dose-finding trial
– Several phase I and phase II studies ongoing
– Refs 62–66
MM-111 ERBB2 and ERBB3 Antitumor activity in preclinical models that are dependent on ERBB2 overexpression (57) – Completed phase I safety and dose-finding trial
– Several phase II studies ongoing
– Refs 52, 53
MM-141 IGF-IR and ERBB3 Prevents PI3K/AKT/mTOR network adaptation by blocking the redundant survival pathways and degrading the RTK complexes (58) – Ongoing phase I study to establish the recommended dose and schedule
– Ref. 67
MEHD7945A EGFR and ERBB3 It has superior antitumor activity against multiple tumor models compared with monospecific antibodies (59) – Completed phase I safety and dose-finding trial, with evidence of anti-tumor activity
– Several phase I and phase II studies ongoing
– Ref. 68
LJM716 ERBB3 It inhibits ligand-induced and ligand-independent ERBB3 dimerization (60) – Completed phase I safety and dose-finding trial, with evidence of antitumor activity
– Several phase I and phase II studies ongoing
– Refs 69, 70
RG7116 (RO5479599) ERBB3 It inhibits xenograft tumor growth and downregulates cell surface ERBB3. Its efficacy is further enhanced in combination with anti-ERBB2 (pertuzumab) antibodies (61) – Completed phase I safety and dose-finding trial, with evidence of antitumor activity
– Several phase I studies ongoing
– Ref. 71
U3-1287 (AMG 888, patritumab) ERBB3 It blocks the upregulation of total and phosphorylated ERBB3 that follows treatment with lapatinib and trastuzumab, and enhances the antitumor action of the combination against trastuzumab-sensitive and -resistant cells (48) – Completed phase I safety and dose-finding trial
– Several phase I, phase II, and phase III studies ongoing
– Ref. 72
Volume 21, Issue 9
