Abstract
Simple SummaryDrug 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.
Highlights
In the last few years, the lack of success of therapeutic approaches for cancer, mainly caused by intrinsic or acquired drug resistance, underlines the importance of the investigation of the underlying molecular mechanisms and potential therapeutic targets associated with the progress of tumours [1]
The phosphatidylinositol-3-kinase phosphoinositide 3-kinases (PI3Ks)/Akt/mammalian target of the rapamycin pathway is one of the most frequently activated intracellular pathways, which is commonly involved as a balancer for human cancer [2]
phosphatase and tensin homolog (PTEN) and by activating the Akt pathway [99]. These findings indicate a new starting point to overcome drug resistance based on strategies that target the implicated miRNAs
Summary
In the last few years, the lack of success of therapeutic approaches for cancer, mainly caused by intrinsic or acquired drug resistance, underlines the importance of the investigation of the underlying molecular mechanisms and potential therapeutic targets associated with the progress of tumours [1]. PTEN and by activating the Akt pathway [99] In the whole, these findings indicate a new starting point to overcome drug resistance based on strategies that target the implicated miRNAs. RCC: renal cell carcinoma; FLOT1: flotillin-1; FOXO3a: (Forkhead Transcription Factor O Subfamily Member 3a); PTEN: phosphatase and tension homolog deleted on chromosome 10; PKD1: polycystic kidney disease 1; PDGFR: platelet-derived growth factor receptor; MET: tyrosine-protein kinase Met; TWIST1: oncoprotein with important roles in the epithelial to mesenchymal transition process; YAP1: Yes-associated protein 1; PIK3CA: enzymatic subunit p110α of phosphatidylinositol 3-kinase; TSC1: tuberous sclerosis complex 1; RUNX-1: runt-related transcription factor 1; HIPK2: homeodomain-interacting protein kinase-2; MDR1: multiple drug resistance protein 1 gene; FZD7: frizzled class receptor 7; BTG2: B-cell translocation gene 2. Given the complexity and heterogeneity of tumour cells, the effects exerted by miRNAs on drug resistance depends on the different kinds of tumours and differ from tumour to tumour [147]
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