RESEARCH CHALLENGES IN STAGE III AND IV RAS-ASSOCIATED CANCERS: A Narrative Review of the Complexities and Functions of the Family of Genes and Ras Proteins in Housekeeping and Tumorigenesis.

Proto-oncogenes in the superfamily play dual roles in maintaining cellular homeostasis, such as regulating growth signals and contributing to cancer development through proliferation and deregulation. Activating proto-oncogenes in vitro transforms cells, underscoring their centrality in gene regulation and cellular networks. Despite decades of research, poor outcomes in advanced cancers reveal gaps in understanding Ras-driven mechanisms or therapeutic strategies. This narrative review examines genes and Ras proteins in both housekeeping functions, such as cell growth, apoptosis, and protein trafficking, as well as in tumorigenesis, integrating insights from human (, , ), mouse (, , ), and () models. While mutations are tightly linked to human tumors, the interplay between their standard and oncogenic functions remains complex. Even within the same tissue, distinct cancer pathways-such as the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways-can drive varied disease courses, complicating treatment. Advanced-stage cancers add further challenges, including heterogeneity, protective microenvironments, drug resistance, and adaptive progression. This synthesis organizes current knowledge of RAS gene regulation and Ras protein function from genomic alterations and intracellular signaling to membrane dynamics and extracellular interactions, offering a layered perspective on the Ras pathway's role in both housekeeping and tumorigenic contexts.