Signaling Pathways in Glioblastoma: A Convergence of Pathways and a Convergence of Hope

Glioblastoma (GBM) is one of the most aggressive and treatment-resistant cancers, with a median survival of just 14 months despite advances in therapy[1]. The review article “Understanding and Exploiting Cell Signaling Convergence Nodes and Pathway Crosstalk in Malignant Brain Cancer” [2] dives into the complex molecular mechanisms driving GBM progression and treatment resistance, focusing on three key signaling pathways: PI3K, MAPK, and cAMP.

The Complexity of Glioblastoma: Resistant and Persistent

GBM is characterized by intertumoral heterogeneity, meaning that different regions of the tumor may exhibit distinct genetic and molecular profiles. This heterogeneity complicates treatment, as therapies targeting one pathway may fail due to compensatory activation of another. The Cancer Genome Atlas has classified GBM into four molecular subtypes:

1. Classical – Driven by EGFR amplification.
2. Mesenchymal – Associated with NF1 and PTEN mutations.
3. Proneural – Linked to PDGFRA amplification and IDH1 mutations.
4. Neural – Lacks clear driver mutations but expresses neuronal markers[2].

Each subtype responds differently to treatment, creating an increased need for personalized therapeutic strategies.

Key Signaling Pathways in GBM

1. The MAPK Pathway: Cell Proliferation and Survival

The mitogen-activated protein kinase (MAPK) pathway is a critical regulator of cell proliferation, survival, and metastasis. In GBM, this pathway is frequently hyperactivated due to:

• EGFR amplification (seen in ~40% of cases).
• Loss of NF1, a negative regulator that inactivates Ras by converting GTP to GDP.

Upon growth factor binding (e.g., EGF), receptor tyrosine kinases (RTKs) dimerize and phosphorylate downstream adaptor proteins, leading to Ras → Raf → MEK → ERK activation. ERK then translocates to the nucleus, promoting transcription of oncogenes like c-Myc and CREB.

MAPK-based therapeutic implications:

• Vemurafenib, a BRAF inhibitor, has shown promise in GBM patients with BRAF V600Emutations[2].
• However, resistance often arises due to pathway redundancy, where tumors activate alternate survival mechanisms.

2. The PI3K Pathway: Regulating Cell Growth

The phosphoinositide 3-kinase (PI3K) pathway is another major player in GBM, regulating cell growth, metabolism, and survival. Key alterations include:

• PTEN loss, leading to unchecked PIP3 accumulation and AKT/mTOR activation.
• PI3K mutations, driving oncogenic signaling.

PI3K signaling promotes invadopodium formation, enhancing tumor invasiveness by upregulating matrix metalloproteinases (MMPs).

PI3K-based therapeutic implications:

• BKM120 is a PI3K inhibitor, which could be used as a potential therapy.
• Combining PI3K inhibitors with MAPK inhibitors may prevent resistance by blocking compensatory signaling[2].

3. The cAMP Pathway: Tumor Suppression

Unlike MAPK and PI3K, the cAMP pathway is generally suppressed in GBM, correlating with higher tumor malignancy. cAMP, produced by adenylate cyclase, activates protein kinase A (PKA), which can:

• Inhibit Raf, suppressing MAPK signaling.
• Induce apoptosis via Bim upregulation.

Therapeutic implications:

• PDE inhibitors (e.g., IBMX) increase cAMP levels, promoting apoptosis in some GBM cell lines.
• Combining cAMP activators with MAPK inhibitors may overcome resistance in tumors with high ERK activity[2].

Pathway Convergence: CREB as a Critical Molecule

A major theme in the review is pathway convergence on transcription factors like CREB (cAMP response element-binding protein) [2]. CREB integrates signals from MAPK (via ERK phosphorylation of Ser133), PI3K (via RSK and MSK kinases), and cAMP (via PKA).

CREB regulates genes involved in cell survival, proliferation, and stemness, making it an attractive therapeutic target. Small-molecule CREB inhibitors are being explored in leukemia and lung cancer, suggesting potential applicability in GBM[2].

Overcoming Drug Resistance: The Need for Combinatorial Therapy

A major challenge in GBM treatment is adaptive resistance, where tumors rewire signaling networks to bypass targeted inhibition. Strategies to overcome this include:

1. Dual PI3K/MAPK inhibition – Prevents compensatory pathway activation.
2. Targeting downstream molecules – Blocks multiple oncogenic signals simultaneously by targeting factors like CREB.
3. Combining pathway inhibitors with immunotherapy – Enhances anti-tumor immune responses[2].

Toward Precision Medicine in GBM

Understanding signaling crosstalk can inform better therapies for GBM. Future research should focus on identifying biomarkers to predict drug response and developing inhibitors targeting signaling hubs like CREB. For now, this review emphasizes the importance of understanding the convergence of pathways in tackling one of the most formidable challenges in neuro-oncology.

This article provides a fascinating glimpse into the molecular battlefield of GBM and the innovative strategies being developed to fight it. It’s a powerful reminder that cancer is not just a genetic disease, but a signaling disease—and defeating it will require disrupting its communication networks at multiple levels.

Glioblastoma is one of the most aggressive and treatment-resistant cancers AND is driven by hyperactive PI3K and MAPK signaling pathways that promote tumor growth and invasion. BUT these pathways exhibit crosstalk and redundancy, leading to drug resistance. THEREFORE, targeting downstream convergence points like CREB or using combination therapies may overcome resistance and improve treatment outcomes.

References

[1]       “About Glioblastoma,” National Brain Tumor Society. Accessed: Apr. 29, 2025. [Online]. Available: https://braintumor.org/events/glioblastoma-awareness-day/about-glioblastoma/

[2]       N. H. Fung et al., “Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer,” Cell. Signal., vol. 57, pp. 2–9, May 2019, doi: 10.1016/j.cellsig.2019.01.011.