Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products

Iksen, Iksen; Pothongsrisit, Sutthaorn; Pongrakhananon, Varisa

doi:10.3390/molecules26134100

Cited by 137 publications

(81 citation statements)

References 211 publications

(237 reference statements)

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“…Activation of the oncogenic PI3K/AKT/mTOR pathway mediates tumorigenesis and resistance to EGFR TKIs in NSCLC 16–19 . Since PDK1 represents a pivotal node in this important signaling axis, we analyzed the phosphorylation status of its major signaling effectors in NCI-H1975, NCI-H1975/OSIR, H1975-OsiR-PDK-/- and H1975-OsiR-PDK1++/++ clones.…”

Section: Resultsmentioning

confidence: 99%

“…PDK1 is a pivotal node in the oncogenic PI3K/AKT/mTOR pathway 20,21 , which mediates tumorigenesis and resistance to EGFR tyrosine kinase inhibitors in NSCLC 16–19 . Osimertinib had no effect on AKT expression levels, which was similar in both PDK1 knock out and overexpressing clones.…”

Section: Discussionmentioning

confidence: 99%

“…This obstacle to long-term patient survival highlights the need to identify acquired resistance mechanisms. Acquired drug resistance is a complex problem as multiple downstream effector proteins in bypass pathways can drive tumor regrowth, progression, and ultimately drug resistance 16–19 .…”

Section: Introductionmentioning

confidence: 99%

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3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

Meraz

Majidi

Fang

et al. 2021

Preprint

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Osimertinib sensitive and resistant NSCLC NCI-H1975 clones were used to model osimertinib acquired resistance in humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation were found in resistant clones. Resistant tumors in humanized mice were initially partially responsive to osimertinib, then aggressive tumor regrowth occurred accompanied by an immunosuppressive tumor microenvironment. 3-phosphoinositide-dependent kinase 1 (PDK1) was identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitized resistant clones and a patient derived xenograft (PDX) with acquired resistance to osimertinib. PDK1 knock-out dysregulated PI3K/Akt/mTOR signaling, promoted cell cycle arrest at the G1 phase, and inhibited nuclear translocation of yes-associated protein (YAP). Higher expression of PDK1 was found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

Meraz

Majidi

Fang

et al. 2021

Preprint

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“…The current commercially accessible targeted inhibitors for cancer patients with abnormal activation of the PI3K/AKT/mTOR pathway include everolimus (mTOR inhibitor), sirolimus (mTOR inhibitor), temsirolimus (mTOR inhibitor), alpelisib (PI3K inhibitor), duvelisib (PI3K inhibitor), copanlisib (PI3K inhibitor), idelalisib (PI3K inhibitor), umbralisib (PI3K inhibitor). Phase III clinical trials of AKT inhibitors, such as capivasertib and ipatasertib, have been proceeded in cancer ( Figure 1 and Table 1 ) ( 6 , 16 , 17 ). Preclinical and clinical trials have shown encouraging outcomes for these targeted medicines.…”

Section: Introductionmentioning

confidence: 99%

PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

et al. 2022

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Cancer is a severe public health issue that is a leading cause of mortality globally. It is also an impediment to improving life expectancy worldwide. Furthermore, the global burden of cancer incidence and death is continuously growing. Current therapeutic options are insufficient for patients, and tumor complexity and heterogeneity necessitate customized medicine or targeted therapy. It is critical to identify potential cancer therapeutic targets. Aberrant activation of the PI3K/AKT/mTOR pathway has a significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR pathway alterations in cancer and various cancer hallmarks associated with the PI3K/AKT/mTOR pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), and chemoresistance. Importantly, this review provided recent advances in PI3K/AKT/mTOR inhibitor research. Overall, an in-depth understanding of the association between the PI3K/AKT/mTOR pathway and tumorigenesis and the development of therapies targeting the PI3K/AKT/mTOR pathway will help make clinical decisions.

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“…As we all known, PI3K/AKT signaling pathway has been widely reported to be one of the most common and important pathways for cancers [34][35][36]. The pathway includes multiple core components and is controlled at multiple levels.…”

Section: Discussionmentioning

confidence: 99%

RPS15A promotes the proliferation and migration of nasopharyngeal carcinoma

Bian

Niu

2022

Preprint

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Background: Nasopharyngeal carcinoma (NPC) is an epithelial squamous cell carcinoma arising from the nasopharyngeal mucosal lining. Ribosomal protein S15a (RPS15A) plays vital role in protein translation and was recently reported to be an oncogene in numerous tumor types. However, its biological role in NPC is remain largely unclear.Methods: In this study, we explored the expression of RPS15A in NPC tissues by immunofluorescence histochemical staining (IHC) staining of human tissue microarray. The C666-1 and CNE-2Z NPC cell lines with RPS15A depletion were used to investigate the effects of RPS15A on NPC cell proliferation, migration and apoptosis. In vivo tumor growth of NPC cells was observed by subcutaneous xenograft mice model. The potential mechanism was explored by Human Apoptosis Antibody Array analysis and WB experiments. Results: RPS15A was significantly up-regulated in NPC and RPS15A knockdown remarkably suppressed NPC cells proliferation, migration and induced cell apoptosis. Moreover, RPS15A silencing also impaired tumor growth of xenograft mice. Further Human Apoptosis Antibody Array analysis indicated that depletion of RPS15A could promote several apoptosis-related proteins expression, and results of WB experiments confirmed the inhibition of PI3K/AKT pathway. Conclusion: RPS15A knockdown suppressed proliferation, migration and increased apoptosis of NCP cells by inhibiting PI3K/AKT signaling pathway. RPS15A may serve as a promising therapeutic target for NPC patients.

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Targeting the PI3K/AKT/mTOR Signaling Pathway in Lung Cancer: An Update Regarding Potential Drugs and Natural Products

Cited by 137 publications

References 211 publications

3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

RPS15A promotes the proliferation and migration of nasopharyngeal carcinoma

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