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Eurasian Journal of Medicine and
Oncology
Cancer pathway ranking through odds ratios

one indicates the protein’s inclusion in the pathway, while breast cancer. The identification of PIK3CA as a central
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0 indicates its absence. protein in zone 1 aligns with these findings, suggesting
that targeting PI3K-AKT signaling in the network core
4. Discussion could yield similar benefits in other cancers, such as lung

This study provides a comprehensive understanding of the cancer. Furthermore, TNF inhibitors, such as infliximab
centrality of cancer signaling pathways within large PPINs, and etanercept, are widely used to treat inflammatory
comprising 9448 proteins organized into six distinct zones conditions like rheumatoid arthritis and Crohn’s disease.
based on their proximity to the network center. Analysis of Emerging evidence suggests that these agents may also
the innermost zones (zones 1 and 2) uncovered a significant have anti-cancer effects, particularly in cancers driven by
enrichment of cancer-related signaling pathways, including chronic inflammation. For instance, preclinical studies have
PI3K-AKT, TNF signaling, JAK-STAT, mTOR, and Wnt shown that TNF inhibition can suppress tumor growth and
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pathways. These findings highlight the critical roles of metastasis in models of lung cancer. The findings in this
central proteins in oncogenic processes and offer valuable study highlight the potential of targeting TNF signaling in
insights into cancer biology. the network core to disrupt inflammatory responses that
fuel cancer progression.
Zones 1 and 2, collectively representing the network’s
core, exhibit a dense concentration of cancer-associated The identification of ten highly influential proteins,
pathways. Proteins in these zones likely serve as key hubs predominantly involved in PI3K-AKT and mTOR signaling,
for signal transduction, underscoring their importance underscores a convergence of critical pathways that sustain
in tumor progression and survival. Notably, the PI3K- cancer cell viability. Proteins like AKT serine/threonine
AKT pathway accounts for 51% of signaling proteins in kinase 1 (AKT1), PIK3CA, and protein kinase C alpha
zone 1, highlighting its central role in regulating cancer (PRKCA) exemplify master regulators whose dysregulation
cell survival and proliferation. This high representation drives key oncogenic processes, including cell survival,
suggests a direct correlation between pathway centrality metabolic reprogramming, and resistance to apoptosis.
and functional significance in oncogenesis. Specifically, mutations or overactivation of these proteins
are frequently observed in various cancers, including lung
In contrast, the TNF pathway displays a pronounced cancer, highlighting their therapeutic potential. Son of
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preference for zone 1, with an OR of 4.22, indicating a sevenless homolog 2 (SOS2) is involved in the Ras signaling
significantly higher likelihood of being localized in the pathway, which is crucial for cell growth and survival, and
network core. This aligns with TNF’s well-established role its dysregulation can contribute to tumorigenesis. AKT1
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in modulating inflammatory responses that are intricately is a critical regulator of cell survival and growth, frequently
linked to cancer progression. The distinct enrichment activated in cancer cells, contributing to oncogenesis and
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patterns of these pathways suggest a functional classification resistance to apoptosis. PIK3CA, a key component of the
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within the network, where certain pathways are more PI3K-AKT pathway, regulates cell growth, proliferation,
central to core biological processes like survival, while and survival, with mutations frequently observed in
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others contribute to peripheral signaling roles. Targeting cancers. AKT serine/threonine kinase 2 (AKT2) has a
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TNF signaling could disrupt multiple oncogenic processes role in glucose metabolism, cell proliferation, and survival,
simultaneously, making it a promising therapeutic strategy. with its overactivation implicated in cancer, particularly in
Interestingly, while the PI3K-AKT pathway shows a metastasis and resistance to chemotherapy. 33,34 AKT serine/
slightly lower probability (OR: 0.87) of zone 1 association, it threonine kinase 3 (AKT3) has been shown to contribute
remains a dominant regulator across zones. Other pathways, to cell survival and cancer progression, with distinct roles
such as JAK-STAT, mTOR, and Wnt pathways, show only in brain and lung cancers. Phosphatidylinositol-4,5-
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slight variations between zones, with OR values close to 1. bisphosphate 3-kinase catalytic subunit beta (PIK3CB)
However, the pronounced presence of the TNF pathway in supports cell growth and survival by activating the
zone 1 strengthens its role in cancer progression and cell PI3K-AKT pathway and is linked to tumorigenesis and
survival. In addition, Alpelisib, a PI3Kα inhibitor, has metastasis in several cancers, including lung cancer.
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shown significant efficacy in treating hormone receptor- Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic
positive, human epidermal growth factor receptor 2 subunit delta (PIK3CD) is involved in immune cell
(HER2)-negative breast cancer with phosphatidylinositol- function and also plays a role in cancer, particularly in
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4,5-bisphosphate 3-kinase catalytic subunit alpha B-cell malignancies and lung cancer. Phosphoinositide-3-
(PIK3CA) mutations. Clinical trials demonstrated that kinase regulatory subunit 2 (PIK3R2), a regulatory subunit
combining alpelisib with fulvestrant improves progression- in the PI3K pathway, is linked to cancer cell proliferation,
free survival in patients with PIK3CA-mutated advanced survival, and migration. Phosphoinositide-3-kinase
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Volume 9 Issue 2 (2025) 83 doi: 10.36922/ejmo.8082