Histological Transformation to Gliosarcoma With Combined BRAF/MEK Inhibition in BRAF V600E Mutated Glioblastoma

Authors

Blessie Elizabeth Nelson
Neha K Reddy
Jason T Huse
Behrang Amini
Mirella Nardo
Mohamed Gouda
Shiao-Pei Weathers
Vivek Subbiah

Publication Date

5-25-2023

Journal

NPJ Precision Oncology

Abstract

The identification of BRAF V600 mutation in multiple cancers beyond melanoma and the development of combined BRAF and MEK targeting agents have altered the landscape of tissue-agnostic precision oncology therapies with an impact on survival outcomes. Despite initial efficacy, resistance emerges, and it is pertinent to identify putative resistance mechanisms. We report a case of recurrent glioblastoma (GBM) harboring BRAF V600E alteration who initially responded to combined BRAF + MEK inhibition and subsequently developed treatment resistance by histological transformation to gliosarcoma and acquisition of oncogenic KRAS G12D and an NF1 L1083R mutation. This documented case represents an initial evidence of a developing phenomenon in cancer research as it provides the first evidence of an emergent KRAS G12D/NF1 L1083R aberration with histological transformation occurring concurrently with primary BRAF V600E-altered glioblastoma as a previously unrecognized acquired mechanism of resistance in the setting of combined BRAF and MEK inhibition. This novel finding not only sheds new light on the RAS/MAPK pathway but also highlights the potential for morphological transformation to gliosarcoma, underscoring the critical need for further investigation in this area.

Keywords

CNS cancer, Molecular medicine, Oncogenesis

Comments

Supplementary Materials

PMID: 37231247