HER3/ErbB3, an emerging cancer therapeutic target.
HER3 is a member of the HER (EGFR/ErbB) receptor family consisting of four closely related type 1 transmembrane receptors (EGFR, HER2, HER3, and HER4). HER receptors are part of a complex signaling network intertwined with the Ras/Raf/MAPK, PI3K/AKT, JAK/STAT, and PKC signaling pathways. Aberrant activation of the HER receptors and downstream signaling molecules tips the balance on cellular events, leading to various types of cancers. Monoclonal antibodies (mAbs) and small molecule inhibitors targeting EGFR and HER2 tyrosine kinase activities exhibit clinical benefits in the treatment of several types of cancers, but their clinical efficacy is limited by the occurrence of drug resistance. HER3 is the preferred dimerization partner of HER2 and it is well established that HER3 plays an important role in drug resistance to EGFR- and HER2-targeting therapies. Since HER3 has limited kinase activity, mAbs are being explored to target HER3 for cancer therapy. Currently, approximately a dozen of anti-HER3 mAbs are at different stages of clinical development. However, the lack of established biomarkers has made it more challenging to stratify cancer patients to whom HER3-targeting therapies can be more effective. In this review, we focus on the validation of HER3 as a cancer drug target, the recent development in biomarker discovery for anti-HER3 therapies, and the progress made in the clinical development of HER3-targeting mAbs.
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Ningyan
N
Zhang
PanaMab, Inc., Houston, TX 77021, USA.
Yujun
Y
Chang
Division of Oncology, Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Adan
A
Rios
Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA hiqiang.an@uth.tmc.edu.
Zhiqiang
Z
An
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D014408:Biomarkers, Tumor / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D009154:Mutation; D000075702:Nedd4 Ubiquitin Protein Ligases; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics; D055503:Protein Multimerization; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D056827:Endosomal Sorting Complexes Required for Transport; D020890:Neuregulin-1; D016376:Oligonucleotides, Antisense; D000075702:Nedd4 Ubiquitin Protein Ligases; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3
HER3/ErbB3; biomarkers; cancer therapy; monoclonal antibody (mAb)