Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer

• Published in: BMC medicine 2024-02, Vol.22 (1), p.74-13, Article 74
• Main Authors: Adashek, Jacob J, Pandya, Chinmayi, Maragakis, Nicholas J, De, Pradip, Cohen, Philip R, Kato, Shumei, Kurzrock, Razelle
• Format: Article
• Language: English
• Subjects: ALS19; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Antibodies; Anticancer properties; Antimitotic agents; Antineoplastic agents; Antitumor activity; Breast cancer; Cancer; Care and treatment; Cerebrospinal fluid; Dementia; Diagnosis; Disease; Dosage and administration; Epidermal growth factor; ErbB protein; ErbB-1 protein; ErbB-2 protein; ErbB-3 protein; ERBB4; Feedback loops; Gene mutations; Genetic aspects; Glial cells; Health aspects; Humans; Inhibitors; Isoforms; Kinases; Ligands; Medical research; Musculoskeletal system; Mutation; Neoplasms - genetics; Nervous system; Neuregulin 1; Neuregulin-1 - genetics; Neuregulin-1 - metabolism; Neurological diseases; Neurology; Novel targets; NRG1; Pathogenesis; Receptor, ErbB-4 - genetics; Receptor, ErbB-4 - metabolism; Receptors; Review; Schizophrenia; Signal Transduction; Spinal cord; Therapeutic targets; Toxicity
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-024-03293-3

Neuregulin-1 (NRG1) is implicated in both cancer and neurologic diseases such as amyotrophic lateral sclerosis (ALS); however, to date, there has been little cross-field discussion between neurology and oncology in regard to these genes and their functions. Approximately 0.15-0.5% of cancers harbor NRG1 fusions that upregulate NRG1 activity and hence that of the cognate ERBB3/ERBB4 (HER3/HER4) receptors; abrogating this activity with small molecule inhibitors/antibodies shows preliminary tissue-agnostic anti-cancer activity. Notably, ERBB/HER pharmacologic suppression is devoid of neurologic toxicity. Even so, in ALS, attenuated ERBB4/HER4 receptor activity (due to loss-of-function germline mutations or other mechanisms in sporadic disease) is implicated; indeed, ERBB4/HER4 is designated ALS19. Further, secreted-type NRG1 isoforms may be upregulated (perhaps via a feedback loop) and could contribute to ALS pathogenesis through aberrant glial cell stimulation via enhanced activity of other (e.g., ERBB1-3/HER1-3) receptors and downstream pathways. Hence, pan-ERBB inhibitors, already in use for cancer, may be agents worthy of testing in ALS. Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.