p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector

p70 S6 kinase (p70^S6K) is best known for its regulatory roles in protein synthesis and cell growth by phosphorylating its primary substrate, ribosomal protein S6, upon mitogen stimulation. The enhanced expression/activation of p70^S6K has been correlated with poor prognosis in some cancer types, suggesting that it may serve as a biomarker for disease monitoring. p70^S6K is a critical downstream effector of the oncogenic PI3K/Akt/mTOR pathway and its activation is tightly regulated by an ordered cascade of Ser/Thr phosphorylation events. Nonetheless, it should be noted that other upstream mechanisms regulating p70^S6K at both the post-translational and post-transcriptional levels also exist. Activated p70^S6K could promote various aspects of cancer progression such as epithelial-mesenchymal transition, cancer stemness and drug resistance. Importantly, novel evidence showing that p70^S6K may also regulate different cellular components in the tumor microenvironment will be discussed. Therapeutic targeting of p70^S6K alone or in combination with traditional chemotherapies or other microenvironmental-based drugs such as immunotherapy may represent promising approaches against cancers with aberrant p70^S6K signaling. Currently, the only clinically available p70^S6K inhibitors are rapamycin analogs (rapalogs) which target mTOR. However, there are emerging p70^S6K-selective drugs which are going through active preclinical or clinical trial phases. Moreover, various screening strategies have been used for the discovery of novel p70^S6K inhibitors, hence bringing new insights for p70^S6K-targeted therapy.