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Published on: October 27, 2014
Histological transformation to gliosarcoma with combined BRAF/MEK inhibition in BRAF V600E mutated glioblastoma
Blessie Elizabeth Nelson1, Neha K Reddy2, Jason T Huse3
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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.
Insights
BRAF V600E-mutated glioblastoma initially responded to targeted therapy but developed resistance. This resistance involved transformation to gliosarcoma and new KRAS G12D/NF1 L1083R mutations, revealing a novel resistance mechanism.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- BRAF V600 mutations are key targets in precision oncology, particularly in glioblastoma (GBM).
- Combined BRAF and MEK inhibition offers therapeutic benefits but faces challenges due to emerging resistance.
- Understanding resistance mechanisms is crucial for improving long-term patient outcomes.
Purpose of the Study:
- To report a novel mechanism of acquired resistance to BRAF/MEK inhibition in BRAF V600E-mutated glioblastoma.
- To investigate the molecular and histological changes associated with treatment resistance.
Main Methods:
- Case report of a patient with recurrent glioblastoma harboring BRAF V600E.
- Analysis of histological transformation and acquisition of new mutations (KRAS G12D, NF1 L1083R) after combined BRAF and MEK inhibition.
Main Results:
- The patient initially responded to BRAF/MEK inhibition.
- Resistance developed, characterized by histological transformation to gliosarcoma.
- Acquisition of oncogenic KRAS G12D and NF1 L1083R mutations was observed concurrently with transformation.
Conclusions:
- This case provides the first evidence of emergent KRAS G12D/NF1 L1083R mutations and histological transformation to gliosarcoma as a resistance mechanism to BRAF/MEK inhibition in BRAF V600E glioblastoma.
- These findings highlight a new aspect of RAS/MAPK pathway alterations and potential morphological changes.
- Further research is needed to explore this phenomenon and its clinical implications.
