p70S6 Kinase as a Key Regulator of Cancer Cell Growth and Proliferation

Abstract

p70S6 kinase 1 (p70S6K1), encoded by RPS6KB1, is a serine/threonine kinase within the PI3K/AKT/mTOR signaling network that regulates protein synthesis, cell growth, metabolism, and other processes relevant to cancer progression. Its activity is controlled by multisite phosphorylation involving mTORC1, phosphoinositide-dependent kinases-1 (PDK1), and additional regulatory inputs, and therefore changes in p70S6K phosphorylation or abundance may have context-dependent biological and clinical consequences. Increasing evidence links aberrant p70S6K signaling with epithelial–mesenchymal transition, cancer stemness, therapeutic resistance, angiogenesis, and metabolic adaptation in selected malignancies. In addition to cell-autonomous effects within tumor cells, emerging studies suggest that p70S6K signaling participates in interactions between tumor cells and components of the tumor microenvironment (TME), including immune cells, adipocytes, fibroblasts, and endothelial cells. These non-cell-autonomous functions represent an important and comparatively less explored dimension of p70S6K biology. Therapeutic approaches targeting this pathway include direct p70S6K inhibitors, dual or multitarget kinase inhibitors, upstream mTOR/PI3K/AKT pathway inhibitors, RNA-based approaches, and emerging computational and protein-degradation strategies. Importantly, these approaches differ substantially in target selectivity, pharmacological development, and clinical evidence and should therefore not be considered equivalent. This review integrates the molecular regulation and cancer-associated functions of p70S6K with current therapeutic strategies, with particular emphasis on tumor–microenvironment interactions, the distinction between direct and indirect pathway inhibition, and the translational barriers that have limited the development of p70S6K-directed therapies.

Last but not least, a number of researchers have examined how p70S6K affects the tumor microenvironment and have suggested that p70S6K may encourage cancer via non-cell-autonomous processes. Few newly developed selective p70S6K inhibitors are presently undergoing preclinical or clinical studies, and the majority of current clinical approaches make use of mTOR inhibitors like rapamycin. Therefore, the goal of this review is to explore p70S6K as a potentially complex therapeutic target in cancer therapy and to summarize and describe the molecular mechanisms controlling the oncogenic activities of, and the therapeutic potential of p70S6K.