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Differential kinase activity of ACVR1 G328V and R206H mutations with implications to possible T?RI cross-talk in diffuse intrinsic pontine glioma.

ABSTRACT: 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 T?RI pathways and known and predicted off-targets of ACVR1 inhibitors, we further validated the inhibition effects of several T?RI 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 T?RI inhibition than SF8628 cells harboring the H3.3K27M mutation and wild-type ACVR1. Thus, inhibition of hidden oncogenic signaling pathways in DIPG such as T?RI that are not limited to ACVR1 itself may provide alternative entry points for DIPG therapeutics.

SUBMITTER: Cao H

PROVIDER: S-EPMC7145857 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Differential kinase activity of ACVR1 G328V and R206H mutations with implications to possible TβRI cross-talk in diffuse intrinsic pontine glioma.

Cao Hongnan H Jin Miao M Gao Mu M Zhou Hongyi H Tao Yizhi Jane YJ Skolnick Jeffrey J

Scientific reports 20200409 1

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 act ...[more]

PMID: 32273545

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Project description:Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II-IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III-IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II-IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas.

Dataset Information

Differential kinase activity of ACVR1 G328V and R206H mutations with implications to possible T?RI cross-talk in diffuse intrinsic pontine glioma.

Publications

Differential kinase activity of ACVR1 G328V and R206H mutations with implications to possible TβRI cross-talk in diffuse intrinsic pontine glioma.

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