PDF(Pubmed)
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.
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.
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.
摘要：
背景：神经调节蛋白-1（NRG1）与癌症和神经疾病如肌萎缩侧索硬化症（ALS）有关；然而，到目前为止,关于这些基因及其功能，神经学和肿瘤学之间几乎没有跨领域的讨论。
方法：大约0.15-0.5％的癌症具有上调NRG1活性的NRG1融合体，从而上调同源ERBB3/ERBB4（HER3/HER4）受体的活性；用小分子抑制剂/抗体消除这种活性显示出初步的组织不可知的抗癌活性。值得注意的是,ERBB/HER药物抑制没有神经毒性。即便如此,在ALS中,减弱的ERBB4/HER4受体活性（由于功能丧失种系突变或散发性疾病的其他机制）是有牵连的;ERBB4/HER4被命名为ALS19。Further,分泌型NRG1亚型可能上调（可能通过反馈回路），并且可能通过其他细胞的活性增强，通过异常神经胶质细胞刺激促进ALS发病机理（例如，ERBB1-3/HER1-3)受体和下游途径。因此，泛ERBB抑制剂，已经用于癌症，可能是值得在ALS中测试的药物。
结论：癌症和ALS之间的共同信号级联可能代表了两种疾病的新治疗靶标。
方法：大约0.15-0.5％的癌症具有上调NRG1活性的NRG1融合体，从而上调同源ERBB3/ERBB4（HER3/HER4）受体的活性；用小分子抑制剂/抗体消除这种活性显示出初步的组织不可知的抗癌活性。值得注意的是,ERBB/HER药物抑制没有神经毒性。即便如此,在ALS中,减弱的ERBB4/HER4受体活性（由于功能丧失种系突变或散发性疾病的其他机制）是有牵连的;ERBB4/HER4被命名为ALS19。Further,分泌型NRG1亚型可能上调（可能通过反馈回路），并且可能通过其他细胞的活性增强，通过异常神经胶质细胞刺激促进ALS发病机理（例如，ERBB1-3/HER1-3)受体和下游途径。因此，泛ERBB抑制剂，已经用于癌症，可能是值得在ALS中测试的药物。
结论：癌症和ALS之间的共同信号级联可能代表了两种疾病的新治疗靶标。
