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

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.

Analysis on the pathogenesis and treatment progress of NRG1 fusion-positive non-small cell lung cancer

“…1) The fusion of NRG1 triggers the perpetual activation of select growth signaling pathways, notably the ERBB family (ERBB1, ERBB2, ERBB3, ERBB4) ( 34 ), alongside downstream cascades such as PI3K-AKT and MAPK-ERK ( 35 ). NRG1 can interact with ERBB4 resulting in ERBB2/ERBB4 heterodimers ( 36 ). The interaction of NRG1 with ERBB 4 and ERBB 3 activates cellular signaling pathways, promoting cell growth and differentiation.…”