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- Title
Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer.
- Authors
Adashek, Jacob J.; Pandya, Chinmayi; Maragakis, Nicholas J.; De, Pradip; Cohen, Philip R.; Kato, Shumei; Kurzrock, Razelle
- Abstract
Background: 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. Main body: 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. Conclusion: Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.
- Subjects
AMYOTROPHIC lateral sclerosis; NEUREGULINS; SMALL molecules; NEUROLOGICAL disorders; RILUZOLE; NEUROGLIA; VON Hippel-Lindau disease
- Publication
BMC Medicine, 2024, Vol 22, Issue 1, p1
- ISSN
1741-7015
- Publication type
Article
- DOI
10.1186/s12916-024-03293-3