Cooperative interactions of BRAF~(V600E) kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy

摘要

Although malignant astrocytomas are a leading cause of cancer-related death in children, rational therapeutic strategies are lacking. We previously identified activating mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (BRAF~(T1799A) encoding BRAF~(V600E)) in association with homozygous cyclin-dependent kinase inhibitor 2A {CDKN2A, encoding p14ARF and p16lnk4a) deletions in pediatric infiltrative astrocytomas. Here we report that BRAF~(V600E) expression in neural progenitors (NPs) is insufficient for tumorigen-esis and increases NP cellular differentiation as well as apoptosis. In contrast, astrocytomas are readily generated from NPs with additional Ink4a-Arf deletion. The BRAF~(V600E) inhibitor PLX4720 significantly increased survival of mice after intracranial transplant of genetically relevant murine or human astrocytoma cells. Moreover, combination therapy using PLX4720 plus the Cyclin-dependent kinase (CDK) 4/6-specific inhibitor PD0332991 further extended survival relative to either monotherapy. Our findings indicate a rational therapeutic strategy for treating a subset of pediatric astrocytomas with BRAF~(V600E) mutation and CDKN2A deficiency.