Journal of Cancer Research and Immuno-Oncology
Open Access

The Role of RAS, PI3K, and Wnt Pathways in Cancer Development

Allan Trail^{* *}Correspondence: Allan Trail, Department of Urology, University of Amsterdam, Amsterdam, The Netherlands, Email:

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Description

Cancer is fundamentally a disease of uncontrolled cell growth, and at its essence are molecular alterations that disrupt the normal regulatory mechanisms governing cellular proliferation, differentiation, and survival. These alterations often involve critical signaling pathways that, when mutated or dysregulated, lead to the initiation and progression of tumors. Such pathways are referred to as oncogenic pathways, as they contribute to the development of oncogenesis the process of tumor formation.

Oncogenic pathways are typically involved in the regulation of cell division, survival, motility, and angiogenesis. In normal cells, these pathways are tightly controlled to ensure balanced cellular behavior. However, in cancer, key components of these pathways such as receptors, kinases, transcription factors, and regulators of the cell cycle are often mutated, overexpressed, or silenced, leading to malignant transformation.

This article explores some of the most well-established oncogenic pathways, the genetic alterations that influence their activation, and how these pathways contribute to cancer development. It also discusses the therapeutic opportunities arising from targeting these pathways and the ongoing challenges in developing effective cancer therapies.

RAS-RAF-MEK-ERK pathway in cell proliferation and survival

The RAS-RAF-MEK-ERK pathway, also known as the Mitogen- Activated Protein Kinase (MAPK) pathway, is one of the most well-studied oncogenic pathways in cancer. It plays an important role in regulating cell proliferation, differentiation, and survival. In normal cells, this pathway is activated by growth factors binding to Receptor Tyrosine Kinases (RTKs) on the cell surface, triggering a cascade of phosphorylation events that ultimately activate Extracellular signal-Regulated Kinase (ERK), a key effector that regulates gene expression and cellular growth.

RAS mutations: Mutations in the RAS family of genes (KRAS, and NRAS) are among the most common oncogenic alterations in human cancers, particularly in pancreatic, colorectal, and lung cancers. These mutations typically result in a constitutively active form of the RAS protein, which continuously signals downstream effectors like RAF, regardless of external growth signals.

BRAF mutations: Mutations in BRAF, particularly the V600E mutation, are prevalent in melanoma and other cancers. Mutant BRAF continuously activates MEK and ERK, leading to uncontrolled cell division. Targeted therapies, such as BRAF inhibitors (e.g., vemurafenib), have shown significant efficacy in treating BRAF-mutant cancers.

Therapeutic targeting: Inhibitors of the MAPK pathway, including MEK inhibitors (e.g., trametinib) and ERK inhibitors, are being developed to target cancers with aberrant RAS or RAF signaling. However, challenges remain, including drug resistance and the reactivation of the pathway through compensatory mechanisms.

Role of PI3K-AKT-mTOR in cancer progression

The Phosphoinositide 3-kinase (PI3K)-AKT-mammalian Target Of Rapamycin (mTOR) pathway is another critical oncogenic signaling pathway that regulates cell survival, metabolism, and growth. This pathway is activated by a variety of extracellular signals, including growth factors and hormones, and it promotes anabolic processes, such as protein synthesis, while inhibiting apoptosis (programmed cell death).

PI3K mutations: Mutations in the PI3K gene, particularly in the catalytic subunit PIK3CA, are common in several cancers, including breast, ovarian, and endometrial cancers. These mutations result in constitutive activation of the PI3K enzyme, driving the production of Phosphatidylinositol-3,4,5- triphosphate (PIP3), which activates AKT.

Phosphatase and Tensin Homolog (aPTEN) loss: PTEN is a tumor suppressor that antagonizes the PI3K pathway by dephos- phorylating PIP3, thereby preventing AKT activation. Loss of PTEN function, through mutation or deletion, is a frequent event in cancer and leads to unchecked PI3K-AKT signaling.

Therapeutic targeting: Inhibitors of PI3K, AKT, and mTOR have been developed for the treatment of cancers with aberrant activation of this pathway. However, resistance to these inhibitors often arises, highlighting the complexity of targeting this pathway in cancer therapy.

Wnt/β-catenin pathway

The Wnt/β-catenin signaling pathway is essential for embryonic development and tissue homeostasis but is also frequently implicated in cancer, particularly in colorectal cancer. The pathway regulates cell fate determination, proliferation, and stem cell maintenance.

APC mutations: One of the most common genetic alterations in colorectal cancer involves mutations in the Adenomatous Polyposis Coli (APC) gene, a key negative regulator of the Wnt/ β-catenin pathway. Loss of APC function leads to the accumulation of β-catenin in the cytoplasm and its translocation to the nucleus, where it activates transcription of genes that promote cell proliferation and survival.

Therapeutic targeting: While targeting the Wnt/β-catenin pathway has proven challenging due to the complexity of its regulation, several strategies are being analyzed, including small molecules that disrupt the interaction between β-catenin and its transcriptional coactivators.