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Drug resistance remains one of the major problems in cancer therapy and is responsible for up to 90% of cancer-related deaths. It exists across all types of cancer and treatment; thus, determining how to overcome this problem is a goal that involves understanding biological mechanisms and also includes clinical trials to test new therapeutic strategies. In this review, we will highlight the emerging role of the PI3K/Akt pathway in drug resistance by discussing recent findings of a multi-level deregulation. Combinational and personalized therapies, which should take this pathway into consideration, might provide better treatment strategies and improved efficacy for fighting drug resistance in cancer.

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to the carcinogenesis, proliferation, invasion, and metastasis of tumour cells. A multi-level impairment, involving mutation and genetic alteration, aberrant regulation of miRNAs sequences, and abnormal phosphorylation of cascade factors, has been found in multiple cancer types. The deregulation of this pathway counteracts common therapeutic strategies and contributes to multidrug resistance. In this review, we underline the involvement of this pathway in patho-physiological cell survival mechanisms, emphasizing its key role in the development of drug resistance. We also provide an overview of the potential inhibition strategies currently available.