BRAF600 mutations are known to be primary oncogenic drivers in multiple tumors14. In glioblastoma, it occurs in a small portion of IDH-wild type tumors, corresponding to 8% of the cases15. BRAF-targeted therapy has set precedence in demonstrating overall and progression-free survival benefits in multiple tumor types harboring the BRAF V600E mutation. This led to the agnostic approval of dabrafenib and trametinib by the FDA in June 202216,17. Among adult patients with BRAF V600E mutated brain tumors, 15 of the 31 high-grade glioma patients had an objective response rate (ORR) of 33% with 3 Complete Responses (CR) and 12 PRs while the duration of response among all high-grade tumors was 13.6 months. Median progression-free survival was 3·8 months and overall survival was 17·6 months18. Notably, this patient benefitted from Dabrafenib and Trametinib for 21.4 months higher than the median survival outcomes as noted before.
In melanoma, resistance mechanisms emerging after treatment with BRAF-targeted therapy are well known and they correspond mainly to recovery of MEK/ERK signaling or activation of PI3K/AKT signaling, through BRAF amplification and alternative splicing or alterations in RAS, MEK, and ERK10. The mechanism of drug resistance includes alteration of drug targets, expression of drug pumps, expression of detoxification mechanisms, reduced susceptibility to apoptosis through p53, increased ability to repair DNA damage, and altered proliferation19.
Histologic transformation to small cell lung cancer (SCLC) is a widely known resistance mechanism to epidermal growth factor receptor (EGFR) targeted therapy in Non-Small Cell Lung Cancer (NSCLC) occurring in 3-15% of EGFR aberrated NSCLC20. Patients who undergo histologic transformation to small cell lung cancers have dismal outcomes. A systemic review looking at outcomes demonstrated a median survival of 6 months after SCLC transformation21.
In this patient’s case, acquired mutations in KRAS with oncogenic potential and NF1 with unknown actionability were observed after prolonged exposure to BRAF inhibition along with a morphological transformation to gliosarcoma. Gliosarcoma is a rare histopathological variant of IDH-wildtype GBM and accounts for ~2% of glioblastoma variants. Histopathologically, these tumors demonstrate a combination of glial areas and sarcomatoid and mesenchymal differentiated components. Secondary gliosarcoma usually evolves after treatment of primary glioblastoma. These tumors are distinct from radiation-induced gliosarcoma which occurs after intracranial radiotherapy in patients without any prior presence of glioblastoma22. In our patient, this histological transformation of the right frontal lobe dural lesion to gliosarcoma occurred while on active therapy with dabrafenib and trametinib with initial response and then breakthrough progression with radiological and pathological transformation. It should be noted that on initial diagnosis, the pathology for this tumor raised the possibility of anaplastic pleomorphic xanthoastrocytoma. However, in the 2019 recurrence, this specimen exhibited morphology more consistent with archetypal IDH-wild type glioblastoma. However, the possibility that this tumor may have originated from an anaplastic PXA remains, particularly given the patient’s relatively young age. Furthermore, one must also consider the contiguous situated placement of the lesion’s proximity to the leptomeninges which could be a contributing factor to sarcomatous transformation.
Similar to BRAF, the RAS family of genes also works via Mitogen-activated protein kinases (MAPK) signaling pathways and activates RAF and PI3K downstream in independent pathways. Receptor tyrosine kinase signaling via Insulin-like growth factor 1 receptor (IGF1R) promotes activation of PI3K and phosphorylation of AKT23. This does not affect MAPK as is generally thought, however, MAPK and PI3K pathways jointly regulate Mcl-1 which is an anti-apoptotic factor that may promote cancer cell survival and growth. Thus, MAPK and IGF-1R via PI3K and AKT signaling pathways are both implicated in the development of BRAF inhibitor resistance. In one study in BRAF-resistant melanoma, it was found that a combination of MEK inhibitor with PI3K inhibitor led to tumoricidal effects. This study, however, did not observe the development of new mutations after acquired BRAF resistance24.
Additionally, important to note is that KRAS and BRAF do not typically co-occur in gliomas, but a common finding in GBM is aberrant RAS signaling. One paper looking at factors influencing aberrant RAS signaling found that RAS and BRAF mutations contributed to aberrant RAS signaling in a small portion of GBM25. In our case, given that initially neither aberrations were present on pathology and sequentially BRAF and then KRAS and NF1 were noted, the mechanism through which these mutations were acquired seems to be through reduced susceptibility for apoptosis as well as altered molecular signaling pathways as they are all present in common pathways. One study demonstrated that targeting both pathways through co-inhibition was more efficient in inducing apoptosis than inhibition of each pathway23.
To the best of our knowledge and literature review, this is the first case of BRAF V600E mutated GBM with the acquisition of KRAS G12 D and NF1 L1083R mutation both in the RAS/MAPK pathway and histologic transformation to gliosarcoma as a resistance mechanism to BRAF/MEK inhibition. MAPK pathway recovery may act as a secondary mechanism of resistance in glioblastomas harboring BRAF V600E after the treatment with BRAF inhibitors.