Abstract:

Cancer, a multifaceted disease, arises from a complex interplay of genetic mutations, epigenetic modifications, and proteomic alterations that drive tumor progression and therapeutic resistance. Traditional genomic approaches have identified key oncogenes and tumor suppressors; however, the functional consequences of these alterations at the protein level often remain elusive. Proteogenomics, an integrative approach combining next-generation sequencing and mass spectrometry-based proteomics, bridges this gap by linking genomic aberrations to proteomic changes, enabling a deeper understanding of cancer biology. This review highlights the pivotal role of proteogenomics in unraveling cancer mechanisms, focusing on its contribution to understanding signaling pathways, post-translational modifications (PTMs), and tumor heterogeneity. Proteogenomic studies have elucidated key oncogenic pathways, such as PI3K/AKT/mTOR and MAPK, revealing how dysregulated proteins and PTMs drive tumor growth and therapeutic resistance. The approach has also identified novel biomarkers and molecular subtypes across cancers, facilitating precision medicine. Furthermore, proteogenomics has been instrumental in addressing therapeutic resistance by uncovering compensatory mechanisms, clonal evolution, and proteomic adaptations in resistant tumor cells. Breast cancer and melanoma case studies illustrate its potential in developing combination therapies to counter resistance. With clinical applications advancing, proteogenomics holds promise for transforming cancer treatment through personalized medicine, patient stratification, and biomarker-driven therapies. Integrating multi-omic data provides a dynamic and comprehensive view of tumor biology, paving the way for innovative strategies to improve patient outcomes and combat therapeutic resistance. This review underscores proteogenomics as a cornerstone in the evolving landscape of oncology research.

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