Article: Oncogenic Drivers of Pediatric Low-Grade Glioma (pLGG)

Pediatric low-grade glioma (pLGG) is the most common childhood central nervous system (CNS) tumor type, accounting for approximately 30-40% of all pediatric brain tumors. While classified as low-grade, these tumors can cause significant morbidity due to their location, most commonly in the cerebellum, cerebral hemispheres, deep midline structures, optic pathway, and brainstem.¹ Nonetheless, with available treatments, 20-year survival rates are close to 90%.^2,3

Prognosis in children with pLGG varies depending on molecular drivers and tumor subtype. Children typically require long-term surveillance and treatment to manage tumor progression and recurrence.¹ Identifying the oncogenic factors driving the development, survival, and recurrence of pLGG is central to guiding treatment.

The Role of the Mitogen-Activated Protein Kinase (MAPK) Pathway in pLGG

Oncogenic drivers—genetic alterations that promote tumorigenesis by dysregulating key pathways involved in growth, survival, and proliferation—primarily manifest in pLGG as activating mutations or fusions in the MAPK pathway, a key regulator of cell proliferation, differentiation, and survival.^4,5

The MAPK signaling cascade is composed of a series of kinases that relay signals from cell surface receptors to the nucleus; namely, rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF)— including BRAF, CRAF, and ARAF—mitogen-activated extracellular signal-regulated kinase (MEK), and extracellular signal-regulated kinase (ERK).⁴ In pLGG, mutations or fusions in the MAPK pathway genes lead to constitutive activation, driving uncontrolled tumor growth.⁶

Since nearly all pLGG tumors have MAPK pathway activation, this pathway represents a principal therapeutic target. Targeted inhibitors can effectively block aberrant signaling, offering less toxic and more effective alternatives to conventional chemotherapy and radiation, particularly for tumors with BRAF alterations.⁶

Role of BRAF in MAPK Activation

pLGG includes molecularly defined glioma subgroups driven primarily by single genetic events, with BRAF structural variants being the most common, occurring in ~70% of sporadic cases.¹ All pLGG subgroups have a documented driver mutation in BRAF or a cooperating MAPK pathway protein (RAS, RAF, MEK, ERK),⁴ which can lead to excessive pathway activation, making it a key oncogenic driver in pLGG.^5,6 To date, more than 30 BRAF-associated genetic alterations have been identified in various cancers.⁶ In pLGG, key alterations include both fusions and mutations.

KIAA1549-BRAF is the most common BRAF fusion, occurring in 70–80% of pilocytic astrocytoma—the most frequent pLGG—and in 30–40% of all pLGG tumors.⁴ This fusion replaces the N-terminal auto-regulatory domain of the BRAF gene with a segment of the KIAA1549 gene as its fusion partner, producing a constitutively active BRAF protein. The resulting chronic, low-level MAPK pathway activation promotes slower tumor growth; hence, these fusions are generally associated with a favorable prognosis.⁶

In contrast, BRAF^V600E mutations, found in about 20% of pLGG tumors,⁶ involve a single nucleotide substitution of valine to glutamate at codon 600,⁴ producing strong MAPK activation and more aggressive tumor behavior. V600E mutations are more common in ganglioglioma and pleomorphic xanthoastrocytoma and are associated with higher recurrence rates and worse outcomes.^4,7  

While both fusions and mutations activate the MAPK pathway in patients with pLGG, they differ markedly in biological behavior and clinical implications. Traditional histology may not reliably predict progression and prognosis.⁴ For this reason, identifying the specific BRAF genetic alterations at work in pLGG is essential for guiding treatment decisions and predicting the prognosis.^2,3

Why Is BRAF Relevant as a Therapeutic Target?

pLGG is often described as a “single-pathway” disease due to its near-universal association with activation of the MAPK signaling cascade, most commonly through alterations in the BRAF gene.⁷ This makes BRAF a desirable and actionable therapeutic target. The two main types of BRAF alteration observed in pLGG, fusions and point mutations, both activate the MAPK pathway,⁴ but their distinct characteristics mean they are targeted differently.

BRAF^V600E mutations, though associated with more aggressive tumors and poorer prognoses, have shown sustained clinical responses to BRAF inhibitors such as vemurafenib and dabrafenib.⁷ They also respond to dual BRAF/MEK inhibition, with the MEK inhibitor blocking downstream MAPK signaling that may persist despite BRAF inhibition alone. However, BRAF inhibition has a paradoxical effect in tumors with KIAA1549-BRAF fusions. Instead of shrinking, these tumors have grown in response to treatment. As a result, BRAF inhibitors are not recommended for patients with KIAA1549-BRAF fusions, where they may do harm.⁴

To address this limitation, pan-RAF inhibitors, such as tovorafenib, have been approved or are in development. These agents block mutant and wildtype RAF proteins, effectively targeting BRAF monomers (ie, BRAF^V600E) and RAF dimers such as those formed in BRAF fusions.⁴ Targeting BRAF in conjunction with other RAF proteins gives pan-RAF inhibitors broad activity against both fusions and point mutations, further leveraging the potential of BRAF as a therapeutic target.

References:

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