PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside

Alzahrani, Ali S.

doi:10.1016/j.semcancer.2019.07.009

Cited by 773 publications

(549 citation statements)

References 61 publications

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“…A possible explanation to this phenomenon could be that upon mTORC1 inhibition, PI3K-AKT cell signaling is stimulated and, consequently it may increase the survival of cancer cells (199). All this because rapamycin and its rapalogs selectively target only mTORC1 without affecting mTORC2, such selective inhibition could prompt feedback loops resulting in AKT activation at ser473 (216). However, it is important to highlight once more that there is plenty of information, which suggests that the use of such inhibitors in combination with other drugs could improve clinical outcome; what is more, inhibiting both mTORC1 and mTORC2 could improve the poor response of other inhibitors observed in clinical trials.…”

Section: Mtorc1 As a Therapeutic Targetmentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Section: Mtorc1 As a Therapeutic Targetmentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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“…According to the updated literature, there are four categories of inhibitors targeting PI3K/AKT/mTOR signaling pathway: mTOR inhibitors, PI3K inhibitors, dual mTOR/PI3K inhibitors, and AKT inhibitors. Among these, drugs that block mTOR activity are the most studied [87].…”

Section: Pi3k/akt/mtor Signaling Pathway Inhibitorsmentioning

confidence: 99%

“…(3) mTOR and PI3K Dual Inhibitors mTOR and PI3K dual inhibitors are also applied for USC treatment and have the benefit of blocking the whole signaling pathway without inducing complicated feedback loops, which are often observed in certain malignancies treated with a single inhibitor [99]. The design of dual mTOR and PI3K inhibitors is based on the high-sequence homology of the catalytic region sites in both mTOR and PI3K [87]. The first-in-human phase I clinical trial of the mTOR and PI3K dual inhibitor LY3023414 in patients with advanced solid tumors, including EC (n = 15), was completed by Bendell et al in 2017, and the drug demonstrated strong antitumor activity with favorable safety and pharmacokinetic profiles [100].…”

Section: (2) Pi3k Inhibitorsmentioning

confidence: 99%

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Zhang

Kwan

Wong

et al. 2020

Cancers

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Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer-related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC. Keywords: endometrial cancer; uterine serous carcinomaPrecis: Uterine serous cancer, although rare, is the most lethal type of uterine cancer. It has distinct molecular features and pathogenic pathways compared with other uterine cancer types Cancers 2020, 12, 686 2 of 21 heterogeneity, grade 3 EEC displays dissimilar features. Although a large number of grade 3 EEC cases show a serous-like phenotype, others display unequivocally endometrioid morphology [6,7]. Type II tumors are typically detected in women 70 years or older and carry a poor prognosis, high recurrence frequency, and much lower 5-year survival rate compared with type I tumors. In addition, type II tumors usually lack estrogen/progesterone receptors and do not respond to hormonal fluctuations [5].Among the type II tumors, uterine serous carcinoma (USC) is the most common subtype. This highly aggressive variant accounts for only 10% of all ECs but 80% of all EC-associated deaths [8,9]. The 5-year tumor-specific survival rate is 74% and 33% for early-and late-stage USC patients, respectively (and 89% and 77% for low-and high-grade EEC) [10]. Unlike type I EC, the risk of metastasis and recurrence of USC does not rely on primary tumor size or grade; this trait contributes to a low overall survival rate of 18% to 27%. Complete surgical staging is performed, comprising total hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection, followed by carboplatin and paclitaxel. In light of poor patient survival and high recurrence rates, the development of targeted therapies specific to USC pathway aberrations would aid in its management. However, conducting studies that focus solely on this rare subtype has been a constant challenge, making it difficult to determine optimal treatment strategies [9].

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“…In turn, several inhibitors of the pathway were approved by the Food and Drug Administration [9]. In previous research papers, we demonstrated that PARP inhibition leads to Akt activation resulting in cyto-and mitochondria protecting actions [10].…”

Section: Introductionmentioning

confidence: 99%

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Gallyas

Sümegi

Szabó

2020

Cancers

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Poly(ADP-ribose) polymerase (PARP) inhibitors have recently been introduced in the therapy of several types of cancers not responding to conventional treatments. However, de novo and acquired PARP inhibitor resistance is a significant limiting factor in the clinical therapy, and the underlying mechanisms are not fully understood. Activity of the cytoprotective phosphatidylinositol-3 kinase (PI3K)-Akt pathway is often increased in human cancer that could result from mutation, expressional change, or amplification of upstream growth-related factor signaling elements or elements of the Akt pathway itself. However, PARP-inhibitor-induced activation of the cytoprotective PI3K-Akt pathway is overlooked, although it likely contributes to the development of PARP inhibitor resistance. Here, we briefly summarize the biological role of the PI3K-Akt pathway. Next, we overview the significance of the PARP-Akt interplay in shock, inflammation, cardiac and cerebral reperfusion, and cancer. We also discuss a recently discovered molecular mechanism that explains how PARP inhibition induces Akt activation and may account for apoptosis resistance and mitochondrial protection in oxidative stress and in cancer.

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PI3K/Akt/mTOR inhibitors in cancer: At the bench and bedside

Cited by 773 publications

References 61 publications

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

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