gsk-j4 and Diffuse-Intrinsic-Pontine-Glioma

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain cancer whose median survival time is under one year. The possible roles of the two most common DIPG associated cytoplasmic ACVR1 receptor kinase domain mutants, G328V and R206H, are reexamined in the context of new biochemical results regarding their intrinsic relative ATPase activities. At 37 °C, the G328V mutant displays a 1.8-fold increase in intrinsic kinase activity over wild-type, whereas the R206H mutant shows similar activity. The higher G328V mutant intrinsic kinase activity is consistent with the statistically significant longer overall survival times of DIPG patients harboring ACVR1 G328V tumors. Based on the potential cross-talk between ACVR1 and TβRI pathways and known and predicted off-targets of ACVR1 inhibitors, we further validated the inhibition effects of several TβRI inhibitors on ACVR1 wild-type and G328V mutant patient tumor derived DIPG cell lines at 20-50 µM doses. SU-DIPG-IV cells harboring the histone H3.1K27M and activating ACVR1 G328V mutations appeared to be less susceptible to TβRI inhibition than SF8628 cells harboring the H3.3K27M mutation and wild-type ACVR1. Thus, inhibition of hidden oncogenic signaling pathways in DIPG such as TβRI that are not limited to ACVR1 itself may provide alternative entry points for DIPG therapeutics.

Topics: Activin Receptors, Type I; Benzazepines; Brain Stem Neoplasms; Cell Line, Tumor; Diffuse Intrinsic Pontine Glioma; Dose-Response Relationship, Drug; Humans; Imidazoles; Mutation; Panobinostat; Phosphotransferases; Prognosis; Protein Conformation; Pyrimidines; Quinoxalines; Receptor Cross-Talk; Receptors, Transforming Growth Factor beta

Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG.. GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells.. Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.

Topics: Animals; Benzazepines; Cell Line, Tumor; Diffuse Intrinsic Pontine Glioma; Disease Models, Animal; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Histone Demethylases; Homologous Recombination; Humans; Mice; Prognosis; Pyrimidines; Radiation Tolerance; Radiation-Sensitizing Agents; Xenograft Model Antitumor Assays