ONCOGENE ACTIVATION AND DISRUPTED DNA REPLICATION: MOLECULAR DRIVERS OF CANCER DEVELOPMENT
DOI:
https://doi.org/10.66021/pakmcr1060Keywords:
oncogene activation, DNA replication, replication stress, RAS/MAPK, cancer development, genomic instability, checkpoint kinaseAbstract
Background: Cancer development is a multistep process driven by accumulation of genetic and epigenetic alterations that disrupt normal cellular homeostasis. Two central molecular mechanisms — oncogene activation and disrupted DNA replication — cooperate to initiate and sustain malignant transformation.
Methods: We performed an integrative analysis combining next-generation sequencing (NGS), immunofluorescence microscopy, flow cytometry, Western blotting, and bioinformatic pathway analyses across multiple cancer cell lines and clinical biopsy specimens.
Results: Activated RAS/MAPK and PI3K/AKT signaling was identified in 78% of samples. Replication fork stalling and increased gamma-H2AX foci correlated significantly with oncogene overexpression (p < 0.001). Cell cycle checkpoint proteins, particularly CHK1 and CHK2, were downregulated in high-oncogene-burden specimens, permitting aberrant S-phase progression.
Conclusion: Our findings establish a mechanistic link between oncogene activation and replication stress, providing potential therapeutic targets at the intersection of these two pathways. Inhibitors targeting replication checkpoint kinases may show synergistic efficacy when combined with oncogene-directed therapies.
