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Several molecular pathways have been demonstrated to be involved in the initiation and development of CRC which among them, the overactivation of the phosphatidyl\u2010inositol 3\u2010kinase (PI3K)\/Akt\/mTOR axis is of importance. The current review aims to unravel the mechanisms by which the PI3K\/Akt\/mTOR pathway affects CRC progression; and also, to summarize the original data obtained from international research laboratories on the oncogenic alterations and polymorphisms affecting this pathway in CRC. Besides, we provide a special focus on the regulatory role of noncoding RNAs targeting the PI3K\/Akt\/mTOR pathway in this malignancy. Questions on how this axis is involved in the inhibition of apoptosis, in the induction of drug resistance, and the angiogenesis, epithelial to mesenchymal transition, and metastasis are also responded. We also discussed the PI3K\/Akt pathway\u2010associated prognostic and predictive biomarkers in CRC. In addition, we provide a general overview of PI3K\/Akt\/mTOR pathway inhibition whether by chemical\u2010based drugs or by natural\u2010based medications in the context of CRC, either as monotherapy or in combination with other therapeutic agents; however, those treatments might have life\u2010threatening side effects and toxicities. To the best of our knowledge, the current review is one of the first ones highlighting the emerging roles of nanotechnology to overcome challenges related to CRC therapy in the hope that providing a promising platform for the treatment of CRC.<\/jats:p>","DOI":"10.1002\/jcp.30655","type":"journal-article","created":{"date-parts":[[2021,12,12]],"date-time":"2021-12-12T23:21:20Z","timestamp":1639351280000},"page":"1720-1752","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["The PI3K\/Akt\/mTOR axis in colorectal cancer: Oncogenic alterations, non\u2010coding RNAs, therapeutic opportunities, and the emerging role of nanoparticles"],"prefix":"10.1002","volume":"237","author":[{"given":"Mohammad\u2010Javad","family":"Sanaei","sequence":"first","affiliation":[{"name":"Department of Hematology and Blood Banking School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences  Tehran 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