ERBB4 and neoplasm: The rationale for choosing neratinib was two-fold: i) it inhibits irreversibly erbB1, HER2 and erbB4, and ii) data suggest drug penetration across the BBB.10 Our studies showed minimal tumor growth delay for neratinib alone (Supplemental Fig. 1F),5 which is not-surprising, since HER2-targeted therapies have shown limited efficacy against BM.6,11 Adding macitentan to neratinib did not improve survival, compared to control-treated mice (Supplemental Fig. 1G).5 These data support the hypothesis that the role of the endothelin axis may be more specific to chemoprotection in BM.