Acquired pten loss may mediate dabrafenib and trametinib resistance in braf v600e–mutated epithelioid glioblastoma: a case report

Abstract Epithelioid glioblastoma is a rare variant of glioblastoma that primarily affects children and young adults. This commonly has a BRAF V600E mutation and can be treated with BRAF and MEK inhibitors. CASE DESCRIPTION: An 18-year-old woman was diagnosed with an epithelioid glioblastoma. She received temozolomide chemoradiotherapy. Upon progression she had redo surgery and received dabrafenib and trametinib. The patient developed a drop metastasis to the cervical spine, and consequently received focal radiotherapy, 20 Gy in five fractions. Treatments were halted six months after her second resection due to further disease progression. She developed uncal herniation, requiring her to have a third resection approximately six months after her second resection. She passed away after this, 12 months following her initial diagnosis. Retrospective genetic analysis of three tumor specimens showed a novel PTEN mutation that arose after her first surgery. We suspect that the acquired PTEN mutation conferred resistance to dabrafenib and trametinib. DISCUSSION: This case offers teaching points and research questions. Firstly, early treatment with BRAF and MEK inhibitors in high grade BRAF V600E–mutated gliomas may be optimal as the patient may have stabilized with earlier treatment on dabrafenib and trametinib. Secondly, further studies are required to investigate whether the addition of PTEN mutation to BRAF V600E leads to aggressive tumor behavior. Lastly, there is a need for investigation into potential benefits of treating similar patients by co-targeting the BRAF and PI3K/AKT pathways.