Combined BRAFV600E and MEK blockade for BRAFV600E-mutant gliomas

Abstract

BRAFV600E is a common finding in glioma (about 10–60% depending on histopathologic subclassification). BRAFV600E monotherapy shows modest preclinical efficacy against BRAFV600E gliomas and also induces adverse secondary skin malignancies. Here, we examine the molecular mechanism of intrinsic resistance to BRAFV600E inhibition in glioma. Furthermore, we investigate BRAFV600E/MEK combination therapy that overcomes intrinsic resistance to BRAFV600E inhibitor and also prevents BRAFV600E inhibitor induced secondary malignancies. Immunoblotting and Human Phospho-Receptor Tyrosine Kinase Array assays were used to interrogate MAPK pathway activation. The cellular effect of BRAFV600E and MEK inhibition was determined by WST-1 viability assay and cell cycle analysis. Flanked and orthotopic GBM mouse models were used to investigate the in vivo efficacy of BRAFV600E/MEK combination therapy and the effect on secondary malignancies. BRAFV600E inhibition leads to recovery of ERK phosphorylation. Combined BRAFV600E and MEK inhibition prevents reactivation of the MAPK signaling, which correlates with decreased cell viability and augmented cell cycle arrest. Similarly, mice bearing BRAFV600E glioma showed reduced tumor growth when treated with a combination of BRAFV600E and MEK inhibitor compared to BRAFV600E inhibition alone. Additional benefit of BRAFV600E/MEK inhibition was reflected by reduced cutaneous squamous-cell carcinoma (cSCC) growth (a surrogate for RAS-driven secondary maligancies). In glioma, recovery of MAPK signaling upon BRAF inhibition accounts for intrinsic resistance to BRAFV600E inhibitor. Combined BRAFV600E and MEK inhibition prevents rebound of MAPK activation, resulting in enhanced antitumor efficacy and also reduces the risk of secondary malignancy development.

Oligonucleotide Therapeutics as a New Class of Drugs for Malignant Brain Tumors: Targeting mRNAs, Regulatory RNAs, Mutations, Combinations, and Beyond

“…Although the H3K27M mutation does not provide a direct therapeutic target, downstream effectors such as specific transcription factors (TFs) may be identified as suitable targets. Pediatric high-grade gliomas also commonly harbor IDH1 R132H and BRAF V600E mutations, as well as CDKN2A, NF1, TP53, PDGFRA, PIK3CA, PIK3R1, and FGFR1 alterations and NTRK fusions [ 43 , 44 ], providing further potential therapeutic targets.…”

Liquid biopsy to monitor melanoma patients

“…For example, mutant BRAF has not only been detected in MM (40–60 %) but also in other malignancies, including hairy cell leukemia (100 % of classic cases) , papillary thyroid cancer (55–67 %) , colorectal cancer (5–10 %) , biliary tract tumors (6 %) , multiple myeloma (5 %) , non‐small cell lung cancer (up to 4 %) and to a lesser extent in lymphoproliferative and myeloproliferative disorders, sarcomas, ependymomas, as well as liver, stomach, esophageal, breast and ovarian cancers . It has also been observed in glioma (10–60 %) , gastrointestinal stromal tumor (GIST) (7 %) and in rare histiocytic disorders such as Erdheim‐Chester disease (54 %) and Langerhans cell histiocytosis (38 %) . Therefore, additional malignancies must always be considered.…”

Liquid Biopsy zur Überwachung von Melanompatienten

“…Beispielsweise werden BRAF ‐Mutationen nicht nur bei MM (40–60 %) nachgewiesen , sondern auch bei anderen Malignomen, darunter Haarzell‐Leukämie (100 % der klassischen Fälle) , papilläres Schilddrüsenkarzinom (55–67 %) , Kolorektalkarzinom (5–10 %) , Tumoren der Gallenwege (6 %) , multiples Myelom (5 %) , nicht‐kleinzelliges Bronchialkarzinom (bis zu 4 %) und in geringerem Maß bei lymphproliferativen and myeloproliferativen Störungen, Sarkomen, Ependymomen sowie Leber‐, Magen‐, Ösophagus‐, Mamma‐ und Ovarialkarzinomen . Sie werden außerdem bei Gliomen (10–60 %) , gastrointestinalen Stromatumoren (GIST) (7 %) und in seltenen histiozytären Störungen wie Erdheim‐Chester‐Erkrankung (54 %) und Langerhans‐Zell‐Histiozytose (38 %) gefunden . Daher müssen stets auch andere Malignome in Betracht gezogen werden.…”