Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

Abstract

Oral cancer (OC) is a devastating disease that takes the lives of lots of people globally every year. The current spectrum of treatment modalities does not meet the needs of the patients. The disease heterogeneity demands personalized medicine or targeted therapies. Therefore, there is an urgent need to identify potential targets for the treatment of OC. Abundant evidence has suggested that the components of the protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway are intrinsic factors for carcinogenesis. The AKT protein is central to the proliferation and survival of normal and cancer cells, and its downstream protein, mTOR, also plays an indispensable role in the cellular processes. The wide involvement of the AKT/mTOR pathway has been noted in oral squamous cell carcinoma (OSCC). This axis significantly regulates the various hallmarks of cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, and epithelial-to-mesenchymal transition (EMT). Activated AKT/mTOR signaling is also associated with circadian signaling, chemoresistance and radio-resistance in OC cells. Several miRNAs, circRNAs and lncRNAs also modulate this pathway. The association of this axis with the process of tumorigenesis has culminated in the identification of its specific inhibitors for the prevention and treatment of OC. In this review, we discussed the significance of AKT/mTOR signaling in OC and its potential as a therapeutic target for the management of OC. This article also provided an update on several AKT/mTOR inhibitors that emerged as promising candidates for therapeutic interventions against OC/head and neck cancer (HNC) in clinical studies.

Drug Delivery (Nano)Platforms for Oral and Dental Applications: Tissue Regeneration, Infection Control, and Cancer Management

“…This malignant condition includes cancer of the lip, tongue, mouth, the floor of mouth, and different parts of the oral cavity. [262][263][264] Like other forms of cancer, the aetiology of oral cancer has not been completely elucidated, but it is interesting to mention that, in the light of recent findings, a link between oral microbiota and cancer development has been found. Periodontitis, a disease affecting tooth's supporting tissue, increases the possibility for the development of oral cancer.…”

mTOR Signaling in Pulmonary Vascular Disease: Pathogenic Role and Therapeutic Target

“…Unfortunately, the authors did not attempt to investigate the role of AKT/mTOR in these experiments. Abundant evidence from the published literature demonstrated that components of AKT/mTOR signaling are critical factors for epithelial-to-mesenchymal transition (EMT) during carcinogenesis but some studies also shed a light on the relationships between AKT/mTOR and EndMT [ 158 , 159 , 160 , 161 , 162 ]. Thus, 48-h treatment of HUVEC with TGF-β 1 led to the significant enhancement of EndMT, motility, and migration ability along with the activation of mTORC1/S6K axis [ 163 ].…”

“Complimenting the Complement”: Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma

“…Harnessing these multimodal mechanisms via immunotherapeutics is therefore expected to be beneficial in early and advanced stages of HCC. Utilizing the differential responses, systemic therapies to perturb VEGF-dependent angiogenesis, WNT, PI3K/AKT/mTOR, AMPK, and c-MET pathways in the TME are either approved or in clinical trials ( 104 ). However, Sorafenib, an oral tyrosine kinase inhibitor (TKI), remains the only FDA-approved treatment with survival benefits for HCC.…”