Inhibition of Jumonji Histone Demethylases Selectively Suppresses HER2⁺ Breast Leptomeningeal Carcinomatosis Growth via Inhibition of GMCSF Expression.

Abstract

HER2⁺ breast leptomeningeal carcinomatosis (HER2⁺ LC) occurs when tumor cells spread to cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord, a complication with a dire prognosis. HER2⁺ LC remains incurable, with few treatment options. Currently, much effort is devoted toward development of therapies that target mutations. However, targeting epigenetic or transcriptional states of HER2⁺ LC tumors might efficiently target HER2⁺ LC growth via inhibition of oncogenic signaling; this approach remains promising but is less explored. To test this possibility, we established primary HER2⁺ LC (Lepto) cell lines from nodular HER2⁺ LC tissues. These lines are phenotypically CD326⁺CD49f^-, confirming that they are derived from HER2⁺ LC tumors, and express surface CD44⁺CD24^-, a cancer stem cell (CSC) phenotype. Like CSCs, Lepto lines showed greater drug resistance and more aggressive behavior compared with other HER2⁺ breast cancer lines <i>in vitro</i> and <i>in vivo</i>. Interestingly, the three Lepto lines overexpressed Jumonji domain-containing histone lysine demethylases KDM4A/4C. Treatment with JIB04, a selective inhibitor of Jumonji demethylases, or genetic loss of function of KDM4A/4C induced apoptosis and cell-cycle arrest and reduced Lepto cell viability, tumorsphere formation, regrowth, and invasion <i>in vitro</i>. JIB04 treatment of patient-derived xenograft mouse models <i>in vivo</i> reduced HER2⁺ LC tumor growth and prolonged animal survival. Mechanistically, KDM4A/4C inhibition downregulated GMCSF expression and prevented GMCSF-dependent Lepto cell proliferation. Collectively, these results establish KDM4A/4C as a viable therapeutic target in HER2⁺ LC and spotlight the benefits of targeting the tumorigenic transcriptional network. SIGNIFICANCE: HER2⁺ LC tumors overexpress KDM4A/4C and are sensitive to the Jumonji demethylase inhibitor JIB04, which reduces the viability of primary HER2⁺ LC cells and increases survival in mouse models.