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

Abstract

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 p16Ink4a) deletions in pediatric infiltrative astrocytomas. Here we report that BRAF V600E expression in neural progenitors (NPs) is insufficient for tumorigenesis 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.glioma | protein kinase | tumor suppressor

In vivo models of brain tumors: roles of genetically engineered mouse models in understanding tumor biology and use in preclinical studies

“…We found that treatment with a combination of the BRAF V600E inhibitor PLX4720 and the CDK4/6 inhibitor PD0332991 had synergistic activity against intracranial tumors in vivo [123]. We observed a similar effect in mouse xenografts of genetically relevant human glioma cell lines.…”

BRAF Mutations Open Doors for N-Ethyl-N-Nitrosourea–Induced Gliomagenesis

“…23,24 Moreover, intracranial genetically engineered mouseederived allografts developed using Braf V600E driven, Ink4a-Arf null neural progenitor cells were also sensitive to PLX4720. 18 These results implicate oncogene addiction to BRAF V600E in gliomas, suggesting that the rat gliomas described by Wang et al 1 may be addicted to BRAF mutations as well. 1 Despite the promise of single agentetargeted therapies, drug resistance has limited their therapeutic benefits in melanoma patients.…”

“…Indeed, the BRAFi, PLX4720, has been tested in vivo in combination with radiation in BRAF V600E mutant patient-derived xenografts and in combination with the cyclin-dependent kinase 4/6 inhibitor PD0332991 in BRAF V600E mutant, Ink4a/Arf deleted genetically engineered mouseederived allografts. 18,24 These preclinical studies showed that combination treatment improved survival compared to untreated and PLX4720-treated mice. Nevertheless, all mice eventually succumbed to disease.…”

Approaches Toward Improving the Prognosis of Pediatric Patients With Glioma: Pursuing Mutant Drug Targets With Emerging Small Molecules

“…In addition, PLX4720 has been shown to significantly increase the survival of mice transplanted with human astrocytoma cells, 19 and it has also been demonstrated that using PLX4720 in combination with PD0332991 (a CDK inhibitor) further extends survival relative to either monotherapy alone.…”

“…However, in the context of this review, the V600E BRAF mutation, present in approximately 20% HGA, 19 is an excellent case in point to highlight the way in which paediatric glioma treatment can potentially be enhanced through the design of mutation-specific small molecules (the V600E mutation results in an amino acid substitution at position 600 in BRAF, from valine (V) to glutamic acid (E)). Inhibition of BRAF signalling blocks proliferation of the cancer cells and induces apoptosis, events which have validated V600E BRAF as a therapeutic target.…”