%0 Journal Article
%T Neuregulin-1 and ALS19 (ERBB4): at the crossroads of amyotrophic lateral sclerosis and cancer.
%A Adashek JJ
%A Pandya C
%A Maragakis NJ
%A De P
%A Cohen PR
%A Kato S
%A Kurzrock R
%J BMC Med
%V 22
%N 1
%D 2024 Feb 19
%M 38369520
%F 11.15
%R 10.1186/s12916-024-03293-3
%X 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.
METHODS: 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.
CONCLUSIONS: Common signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.