A comprehensive review of heregulins, HER3, and HER4 as potential therapeutic targets in cancer

Abstract

Heregulins (HRGs) bind to the receptors HER3 or HER4, induce receptor dimerization, and trigger downstream signaling that leads to tumor progression and resistance to targeted therapies. Increased expression of HRGs has been associated with worse clinical prognosis; therefore, attempts to block HRG-dependent tumor growth have been pursued. This manuscript summarizes the function and signaling of HRGs and review the preclinical evidence of its involvement in carcinogenesis, prognosis, and treatment resistance in several malignancies such as colorectal cancer, non-small cell lung cancer, ovarian cancer, and breast cancer. Agents in preclinical development and clinical trials of novel therapeutics targeting HRG-dependent signaling are also discussed, including anti-HER3 and -HER4 antibodies, anti-metalloproteinase agents, and HRG fusion proteins. Although several trials have indicated an acceptable safety profile, translating preclinical findings into clinical practice remains a challenge in this field, possibly due to the complexity of downstream signaling and patterns of HRG, HER3 and HER4 expression in different cancer subtypes. Improving patient selection through biomarkers and understanding the resistance mechanisms may translate into significant clinical benefits in the near future.

Mechanisms of Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3) Action in Human Neoplasia

“…85 The ERBB3 ligands NRG1 and NRG2 drive ERBB3 signaling in a variety of cancers, including breast, ovarian, colorectal, nonesmall-cell lung carcinoma, prostate, and head and neck squamous cell carcinoma, via overexpression and act in an autocrine, juxtacrine, and paracrine manner. 86 The NRG1 and NRG2 genes cause, via alternative splicing and the use of multiple promoters, numerous isoforms. Although incompletely studied, there is evidence indicating that these different NRG isoforms exert different biological effects when they activate ERBB3 signaling.…”

Involvement of the epidermal growth factor receptor in IL‐13–mediated corticosteroid‐resistant airway inflammation

“…45 Such studies would offer the potential of exploiting the array of small molecule drugs and antibodies that have been developed for cancer therapy. 71,75 In summary, our study suggests that the prototypic Type-2 mediator, IL-13, can give rise to both eosinophilic Type-2 and neutrophilic "Type-17" stereotypic responses, the latter being corticosteroid insensitive and mediated by epithelial EGFR signalling rather than classical immunological Th17 signalling. Based on our TA B L E 1 Comparison of ERBB receptor and ligand expression in "IL-13 high" and "IL-17 high" asthma clusters relative to health in the U-BIOPRED cohort n "IL-13 low/IL-17 low" "IL-17 high" "IL-13 high" Note: Numbers are log2 fold change relative to expression in healthy participants; significant changes are highlighted in bold.…”

“…*P < .05, **P < .01 function appears critically involved in reactions that affect cell fate. 71 Its role within this group of severe asthmatics merits further investigation. 41 In support of this suggestion, EGFR signalling is associated with increased PI3Kδ/Akt activation in ovalbumin-induced F I G U R E 7 Topological data analysis of gene expression obtained from bronchial brushings from the U-BIOPRED cohort.…”

Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers

“…While phase 1~3 trials have been opened for various therapeutic anti-HER3 mAbs [25,26], such as patritumab (AMG-888), seribantumab (MM-121), LJM716 and KTN3379, clinical benefit of antibodies has not been reported. Regarding patritumab, the phase 3 HER3-Lung study did not confirm patritumab efficacy because the combination of patritumab + erlotinib resulted in progression-free survival that was similar to placebo + erlotinib (WCLC, 2016), and patritumab + cetuximab + cisplatin or carboplatin was not more effective than cetuximab + cisplatin or carboplatin in the phase 2 HER3-Head and Neck study (ASCO, 2018).…”