Abstract
The high incidence and modest therapeutic outcomes of lung cancer have prompted the identification of cell molecular targets/biomarkers within the complex networks of interactions involved in cell malignancy. Most of the EMT-related regulatory mediators underline patients’ biologic variations, therapeutic refractory events, and tumor cell heterogeneity. Patient stratification based on the understanding of the relevant pathways, such as the PI3K/Akt axis crucial in EMT initiation, could favorably alter disease management. Significant clinical advantage could be expected when overexpressed Akt tyrosine kinase (Akt2) is addressed as a malignant biomarker to guide clinical management decisions, improving prognosis in lung cancer patients. Moreover, one should not miss the opportunity of using it as a druggable target aiming at the inhibition of the downstream complexity that underlies cell proliferation and survival, expression of stemness markers and drug resistance. The value of mTOR, as a downstream target of Akt, and the further activation of EMT transcription factors Twist, Snail and Zeb1 are revisited in this review. An in-depth state-of-the-art assessment provides evidence of its role in the mechanistic inhibition of epithelial markers, such as E-cadherin and miR-200, while inducing the expression of the mesenchymal ones, such as vimentin, N-cadherin, and miR-21. Lastly, evidence suggesting another transcription factor, FOXM1, as the link between the PI3K/Akt and Wnt/β-catenin pathways, prompting cell metabolism through the regulation of p70S6K, is analyzed. A more realistic approach is advised to address unmet clinical needs and support decision making at a clinical level. Taking into consideration several complex intracellular interactions might further improve patient stratification and result in better outcomes.
Highlights
With 2.21 million new cases being diagnosed every year, lung cancer is still the leading cause of cancer-related deaths (1.80 million deaths in 2020) [1]
The latter has emerged as a key checkpoint of interest due to both the frequency of programmed death ligand-1 (PD-L1) expression in lung cancer as well as observed clinical activity using PD-1 pathway inhibitors [6]
We provide evidence for some of the players on lung cancer tumorigenesis that can be valuable tools in lung cancer patients’ stratification
Summary
With 2.21 million new cases being diagnosed every year, lung cancer is still the leading cause of cancer-related deaths (1.80 million deaths in 2020) [1]. 1 (mSin1), Protor 1 (Protein observed with Rictor 1), and a rapamycin-insensitive companion (Rictor) [16,22–24], being, resistant to rapamycin, whereas mTORC1 is inhibited by it [13,24] Within both complexes, mTOR regulates cell growth, cell proliferation, cell motility, protein synthesis and transcription through a cascade of phosphorylation, leading to the target activation, such as S6K and 4E-BP1 [22]. The inhibition of mTORC1 shifted the activation of the PI3K/Akt pathway towards Ras/MAPK, enhancing the activation of both Akt and ERK, as a drug resistance mechanism [33], and the expression of EGFR [34] Both studies have shown the possible role of Akt/mTOR axis as a disease biomarker; the regulation by the interconnection of different signaling pathways jeopardizes its use as a druggable target. Since all EMT-inducing factors have been linked to other tumorigenic features, such as acquisition of stem-like properties, drug and apoptosis resistance, and altered metabolism [37,38,42], one can hypothesize that EMT can be the main mechanism from which all other tumorigenic features originate
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