Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy | Acta Neuropathologica Communications | Full Text

Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy | Acta Neuropathologica Communications | Full Text

Acta Neuropathologica Communications

Dramatic response of BRAF V600E-mutant epithelioid glioblastoma to combination therapy with BRAF and MEK inhibitor: establishment and xenograft of a cell line to predict clinical efficacy

• Yu Kanemaru,
• Manabu NatsumedaEmail authorView ORCID ID profile,
• Masayasu Okada,
• Rie Saito,
• Daiki Kobayashi,
• Takeyoshi Eda,
• Jun Watanabe,
• Shoji Saito,
• Yoshihiro Tsukamoto,
• Makoto Oishi,
• Hirotake Saito,
• Masayuki Nagahashi,
• Takahiro Sasaki,
• Rintaro Hashizume,
• Hidefumi Aoyama,
• Toshifumi Wakai,
• Akiyoshi Kakita and
• Yukihiko Fujii

Acta Neuropathologica Communications20197:119

https://doi.org/10.1186/s40478-019-0774-7

©  The Author(s). 2019

• Received: 8 June 2019
• Accepted: 18 July 2019
• Published: 25 July 2019

Abstract

Epithelioid glioblastoma is a rare aggressive variant of glioblastoma (GBM) characterized by a dismal prognosis of about 6 months and frequent leptomeningeal dissemination. A recent study has revealed that 50% of epithelioid GBMs harbor three genetic alterations – BRAF V600E mutation, TERT promoter mutations, and homozygous deletions of CDKN2A/2B. Emerging evidence support the effectiveness of targeted therapies for brain tumors with BRAF V600E mutation. Here we describe a dramatic radiographical response to combined therapy with BRAF and MEK inhibitors in a patient with epithelioid GBM harboring BRAF V600E mutation, characterized by thick spinal dissemination. From relapsed tumor procured at autopsy, we established a cell line retaining the BRAF V600E mutation, TERTpromoter mutation and CDKN2A/2B loss. Intracranial implantation of these cells into mice resulted in tumors closely resembling the original, characterized by epithelioid tumor cells and dissemination, and invasion into the perivascular spaces. We then confirmed the efficacy of treatment with BRAF and MEK inhibitor both in vitro and in vivo. Epithelioid GBM with BRAFV600E mutation can be considered a good treatment indication for precision medicine, and this patient-derived cell line should be useful for prediction of the tumor response and clarification of its biological characteristics.

Keywords

• Epithelioid glioblastoma
• BRAF V600E
• Targeted therapy
• Precision medicine