BRAFV600E is the most frequent mutation in BRAF (serine/threonine-protein kinase B-raf). It is a proto-oncogene and the most commonly mutated kinase in human cancers. BRAFV600E can be detected in glioma, the most common primary brain tumor across all ages.
The mitogen-activated protein kinase (MAPK) pathway is essential to the regulation of cellular growth, proliferation, and survival. Upstream of BRAF, growth factors binding to receptor tyrosine kinases (RTKs) at the cell surface lead to phosphorylation of RAS proteins. Then it will activate BRAF. Signal transduction continues downstream from BRAF to MAPK kinase (MEK) 1 and MEK2, and finally to ERK. It phosphorylates multiple targets, leading to increased cell survival, proliferation and differentiation. Finally, the V600E mutation results in constitutive activation of BRAF and downstream activation of MEK and ERK, in a RAS-independent manner. Recently, FDA approved Tovorafenib, pan-raf inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pediatric low-grade glioma (LGG).
Tovorafenib is an orally active and selective inhibitor of pan-Raf kinase.
Firstly, Tovorafenib (TAK-580, MLN 2480) has effect on reversing feedback activation of MEK in response to TAK-733. It leads to more concerted MAPK pathway inhibition. Secondly, Tovorafenib inhibits MAPK pathway signaling in BRAF mutant and some RAS mutant preclinical cancer models at concentrations. Meanwhile, it is most potent in BRAF mutant melanoma models but also has single agent activity in some RAS mutant models. Moreover, the combination of MLN2480 with TAK-733 inhibits the growth of a broader range of RAS mutant tumor models than single agent TAK-580, including primary human tumor xenograft models of melanoma and CRC.
To sum up, Tovorafenib is an orally active pan-Raf kinase inhibitor for gliomas research.
References：
[1] Capogiri M, et al. Front Oncol. 2023 Jan 9;12:1074726.
[2] Elizabeth Grace, et al. Mol Cancer Ther (2013) 12 (11_Supplement): C146.