Role and Therapeutic Targeting of the PI3K/Akt/mTOR Signaling Pathway in Skin Cancer: A Review of Current Status and Future Trends on Natural and Synthetic Agents Therapy

Abstract

The mammalian or mechanistic target of rapamycin (mTOR) and associated phosphatidyl-inositiol 3-kinase (PI3K)/protein kinase B (Akt) pathways regulate cell growth, differentiation, migration, and survival, as well as angiogenesis and metabolism. Dysregulation of these pathways is frequently associated with genetic/epigenetic alterations and predicts poor treatment outcomes in a variety of human cancers including cutaneous malignancies like melanoma and non-melanoma skin cancers. Recently, the enhanced understanding of the molecular and genetic basis of skin dysfunction in patients with skin cancers has provided a strong basis for the development of novel therapeutic strategies for these obdurate groups of skin cancers. This review summarizes recent advances in the roles of PI3K/Akt/mTOR and their targets in the development and progression of a broad spectrum of cutaneous cancers and discusses the current progress in preclinical and clinical studies for the development of PI3K/Akt/mTOR targeted therapies with nutraceuticals and synthetic small molecule inhibitors.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…Short treatment of melanoma cells with BRAF inhibitors has led to either augmented EGFR protein level as the result of epigenetic regulation [104] or increased phosphorylation of the baseline EGFR [105]. In addition, EGFR was correlated with resistance to BRAF inhibitors [102,103] by contributing to activity of ERK1/2 and AKT through a physical interaction with urokinase type plasminogen activator receptor (uPAR) in melanoma cells [114,115]. Our study has shown that selected trametinib-resistant cells can adaptively use EGFR, thus providing a therapeutic window for EGFR inhibition as a complementary treatment approach.…”

ANXA6 Contributes to Radioresistance by Promoting Autophagy via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Carcinoma

“…The PI3K/AKT/mTOR pathway is one of the most frequently activated signaling pathways in cancers and is responsible for tumor development, cellular metastasis, and proliferation (Polivka and Janku, 2014;Zhang et al, 2017;Chamcheu et al, 2019). In particular, the PI3K/AKT/mTOR pathway has attracted extensive attention as the modulator of autophagy (Xu et al, 2020).…”

Involvement of Mitochondrial Mechanisms in the Cytostatic Effect of Desethylamiodarone in B16F10 Melanoma Cells

“…Based on the data presented in this study, it is difficult to propose a mechanism that can explain the said multiple effects on several mitochondrial processes. Considering the central role of Ca 2+ in regulating apoptosis and thereby the survival and therapy resistance of cancer cells [ 70 ], it is a limitation of this study that it cannot account for DEA’s effect on intracellular calcium.…”