• Jacob J Adashek, Chinmayi Pandya, Nicholas J Maragakis, Pradip De, Philip R Cohen, Shumei Kato, and Razelle Kurzrock.
• Department of Oncology, The Johns Hopkins Hospital, The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA. jadashek@westernu.edu.
• Bmc Med. 2024 Feb 19; 22 (1): 7474.

BackgroundNeuregulin-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 BodyApproximately 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.ConclusionCommon signaling cascades between cancer and ALS may represent novel therapeutic targets for both diseases.© 2024. The Author(s).

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