Translational Advances in Oncogene and Tumor-Suppressor Gene Research

Abstract

Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.

Keywords: cancer research; emerging technology; molecular pathways; oncogenes; targeted cancer therapy; tumor heterogeneity; tumor microenvironment; tumor-suppressor genes.

Figure 1

Schematic representation of cell-cycle regulation by cyclin-dependent kinases (CDKs), retinoblastoma protein (Rb), and cyclin-dependent kinase inhibitors (CKIs). Progression through the G₁, S, and M phases is driven by the sequential activation of CDKs (CDK4/6, CDK2, and CDK1) in complex with their respective cyclins (cyclin D, E, A, and B), with G₀ as a resting phase outside active cycling. The Rb protein, in its active, hypophosphorylated form binds E2F to block S-phase genes, aided by PPT1, until phosphorylation by CDK4/6-cyclin D and hyperphosphorylation by CDK2-cyclin E deactivates Rb, freeing E2F to turn S-phase-dependent genes on and thus trigger S-phase entry. There are three checkpoints (CP) that regulate the cell cycle: in G₁, Rb halts progression if DNA damage is detected; in G₂, CDK1-cyclin B blocks progression under stress or damage, ensuring proper timing for DNA repair; and in M, CDK1-cyclin B sustains mitosis until chromosome alignment is confirmed. INK4 inhibitors (p16^INK4A, p15^INK4B, p18^INK4C, and p19^INK4D) block CDK4/6 to prevent premature Rb phosphorylation and G₁/S transition, while CIP/KIP inhibitors (p21^CIP1, p27^KIP1 and p57^KIP2) block CDK2 and CDK1 to pause cycle progression under stress or damage, ensuring proper timing for DNA repair and checkpoint function. Created in BioRender. Stojchevski, R. (2025) https://BioRender.com/x80d496.

Figure 2

Key oncogenic signaling pathways. Left: The RAS/ERK/MAPK pathway is initiated when an RTK receptor is activated by extracellular signals, leading to the activation of Ras. Activated Ras recruits Raf kinases (ARAF, BRAF, CRAF/RAF1) to the cell membrane, where they phosphorylate MEK at Ser166 and Ser186. MEK then phosphorylates and activates ERK/MAPK. Activated ERK/MAPK translocates to the nucleus, where it activates transcription factors Elk1-1 and c-MYC, thus promoting cell proliferation. Middle: The PI3K/AKT pathway, like the RAS/ERK/MAPK pathway, is activated through RTK receptors. Activated RTK triggers PI3K, which converts PIP2 into PIP3. PIP3 provides a docking site for PDK1 and mTOR2, which phosphorylate and activate AKT, which then phosphorylates and inhibits TSC2, a negative regulator of mTORC1. This inhibition indirectly activates mTORC1, which promotes cell growth by modulating transcription factors 4E-BP1 and S6K1, key regulators of protein synthesis. Right: The Wnt/β-catenin begins when Wnt ligands bind to the frizzled receptor and LRP co-receptors, activating the Dishevelled protein. Dishevelled inhibits the destruction complex (composed of GSK-3β, Axin, CK1α, and APC), preventing the degradation of β-catenin. This allows β-catenin to accumulate and translocate to the nucleus, where it activates transcription factors TCF and LEF, driving cell proliferation. Created in BioRender. Stojchevski, R. (2025) https://BioRender.com/p57k526.

Figure 3

Mechanisms of action of small-molecule inhibitors, monoclonal antibodies, immune checkpoint inhibitors, and radionuclides in cancer therapy. Small-molecule inhibitors target key receptors and kinases to disrupt signaling pathways and block tumor progression. Monoclonal antibodies recognize and bind specific antigens on tumor cell surface, leading to immune-mediated destruction. Immune checkpoint inhibitors enhance T-cell activity by blocking inhibitory immune signals, restoring the immune system’s ability to recognize and eliminate tumor cells. Radioimmunotherapy combines monoclonal antibodies with radionuclides to selectively deliver cytotoxic radiation to tumor cells, increasing treatment precision while minimizing damage to normal tissues. Created in BioRender. Stojchevski, R. (2025) https://BioRender.com/k49h851.

Figure 4

Liquid biopsy of bodily fluids (blood). Analytes collected through liquid biopsy include circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free RNA (e.g., miRNA, lncRNA, circRNA), extracellular vesicles (EVs), immune cells, and proteins, which are then analyzed using advanced detection techniques such as PCR and next-generation sequencing (NGS) to identify specific cancer markers, even at low abundance. Liquid biopsy enables the discovery of various cancer-related biomarkers, including various genetic mutations, chromosomal abnormalities, DNA methylation patterns, tumor-associated protein expression, and post-translational modifications, such as phosphorylation. Created in BioRender. Stojchevski, R. (2025) https://BioRender.com/h75n317.

Figure 5

Types of cancer vaccines. There are four types of cancer vaccines: cell-based, viral/bacterial-based, peptide-based, and nucleic acid-based vaccines. Cell-based vaccines are prepared using whole tumor cells or tumor cell fragments. which can be injected directly or loaded onto dendritic cells along with adjuvants to enhance their immunogenicity and stimulate a stronger anti-tumor immune response. Viral/bacterial-based vaccines are designed using recombinant viral or bacterial vectors to deliver genetic material encoding cancer-specific proteins or antigens. These vectors infect host cells, enabling the expression of the target antigens and stimulating an immune response against cancer cells. Peptide-based vaccines use short biosynthetic peptides that mimic specific tumor epitopes of tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) to stimulate the immune system to recognize and attack cancer cells at specific tumor sites where the target antigens are expressed. Nucleic acid-based vaccines deliver genetic material (RNA or DNA) that encodes tumor-specific antigens. The RNA or DNA is typically encapsulated in carriers to protect it from degradation and facilitate efficient delivery into the host cells. Once inside, the genetic material is expressed, producing the target antigens, which are then presented to the immune system. This stimulates T and B cells to recognize and attack cancer cells that express these antigens. Created in BioRender. Stojchevski, R. (2025) https://BioRender.com/c04n703.