Dual mTORC1/2 inhibitor AZD2014 diminishes myeloid-derived suppressor cells accumulation in ovarian cancer and delays tumor growth

Pi, Ruyu; Yang, Yang; Li, Hongyi; Shi, Houhui; Liu, Yü; Wang, Xi; An, Tong; Lu, Tianqi; Wei, Yuquan; Zhao, Xia; Wei, Xiawei

doi:10.1016/j.canlet.2021.09.017

Cited by 16 publications

(9 citation statements)

References 41 publications

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“…About one-fifth of these drugs were inhibitors of PI3K/AKT/mTOR signaling pathway. These inhibitors ( 74 – 76 ) were effective for AML of both high- and low-risk groups, and most of them had lower IC 50 in high-risk groups, suggesting that inhibition of the PI3K signaling pathway may provide a new potential approach for AML treatment. At present, pre-clinical studies have shown that these inhibitors could reduce the proliferation and induce apoptosis, and reverse the multidrug resistance of AML ( 77 – 79 ).…”

Section: Discussionmentioning

confidence: 99%

Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia

et al. 2022

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IntroductionThe heterogeneity of treatment response in acute myeloid leukemia (AML) patients poses great challenges for risk scoring and treatment stratification. Carbohydrate metabolism plays a crucial role in response to therapy in AML. In this multicohort study, we investigated whether carbohydrate metabolism related genes (CRGs) could improve prognostic classification and predict response of immunity and treatment in AML patients.MethodsUsing univariate regression and LASSO-Cox stepwise regression analysis, we developed a CRG prognostic signature that consists of 10 genes. Stratified by the median risk score, patients were divided into high-risk group and low-risk group. Using TCGA and GEO public data cohorts and our cohort (1031 non-M3 patients in total), we demonstrated the consistency and accuracy of the CRG score on the predictive performance of AML survival.ResultsThe overall survival (OS) was significantly shorter in high-risk group. Differentially expressed genes (DEGs) were identified in the high-risk group compared to the low-risk group. GO and GSEA analysis showed that the DEGs were mainly involved in immune response signaling pathways. Analysis of tumor-infiltrating immune cells confirmed that the immune microenvironment was strongly suppressed in high-risk group. The results of potential drugs for risk groups showed that inhibitors of carbohydrate metabolism were effective.DiscussionThe CRG signature was involved in immune response in AML. A novel risk model based on CRGs proposed in our study is promising prognostic classifications in AML, which may provide novel insights for developing accurate targeted cancer therapies.

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Section: Discussionmentioning

confidence: 99%

Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia

et al. 2022

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“…AZD2014 is another second-generation mTOR inhibitor that attenuates myeloid-derived suppressor cell recruitment and blocks cell proliferation in ovarian cancer [ 219 ]. AZD2014 increased docetaxel sensitivity and overcame docetaxel resistance in prostate carcinoma cells [ 220 ].…”

Section: Inhibitors Of the Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy

Li²,

Luo

et al. 2022

Mol Biomed

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The PI3K/AKT/mTOR and RAF/MEK/ERK pathways are commonly activated by mutations and chromosomal translocation in vital targets. The PI3K/AKT/mTOR signaling pathway is dysregulated in nearly all kinds of neoplasms, with the component in this pathway alternations. RAF/MEK/ERK signaling cascades are used to conduct signaling from the cell surface to the nucleus to mediate gene expression, cell cycle processes and apoptosis. RAS, B-Raf, PI3K, and PTEN are frequent upstream alternative sites. These mutations resulted in activated cell growth and downregulated cell apoptosis. The two pathways interact with each other to participate in tumorigenesis. PTEN alterations suppress RAF/MEK/ERK pathway activity via AKT phosphorylation and RAS inhibition. Several inhibitors targeting major components of these two pathways have been supported by the FDA. Dozens of agents in these two pathways have attracted great attention and have been assessed in clinical trials. The combination of small molecular inhibitors with traditional regimens has also been explored. Furthermore, dual inhibitors provide new insight into antitumor activity. This review will further comprehensively describe the genetic alterations in normal patients and tumor patients and discuss the role of targeted inhibitors in malignant neoplasm therapy. We hope this review will promote a comprehensive understanding of the role of the PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways in facilitating tumors and will help direct drug selection for tumor therapy.

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“…ABBV-085, an antibody-drug conjugate targeting LRRC15, which is a membrane-bound protein that activates the FAK pathway on spheroids and metastatic cancer cells to promote tumor metastasis, was capable of preventing the metastasis of ovarian cancer in preclinical models (Ray et al 2022). AZD2014, an mTORC1/2 inhibitor, suppressed the accumulation of MDSCs in ovarian cancer ascites, thereby delaying ovarian cancer progression and reducing recurrence by enhancing antitumor immunity (Pi et al 2021) (Table 2).…”

Section: Therapeutic Strategies Targeting Components Of Ovarian Cance...mentioning

confidence: 99%

Friend and foe: the regulation network of ascites components in ovarian cancer progression

Geng

Pan

et al. 2022

J. Cell Commun. Signal.

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The tumor microenvironment (TME) and its complex role in cancer progression have been hotspots of cancer research in recent years. Ascites, which occurs frequently in patients with ovarian cancer especially in advanced stages, represents a unique TME. Malignant ascites contains abundant cellular and acellular components that play important roles in tumorigenesis, growth, metastasis, and chemoresistance of ovarian cancer through complex molecular mechanisms and signaling pathways. As a valuable liquid biopsy sample, ascites fluid is also of great significance for the prognostic analysis of ovarian cancer. The components of ovarian cancer ascites are generally considered to comprise tumor-promoting factors; however, in recent years studies have found that ascites also contains tumor-suppressing factors, raising new perspectives on interactions between ascites and tumors. Malignant ascites directly constitutes the ovarian cancer microenvironment, therefore, the study of its components will aid in the development of new therapeutic strategies. This article reviews the current research on tumor-promoting and tumor-suppressing factors and molecular mechanisms of their actions in ovarian cancer-derived ascites and therapeutic strategies targeting ascites, which may provide references for the development of novel therapeutic targets for ovarian cancer in the future.

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Dual mTORC1/2 inhibitor AZD2014 diminishes myeloid-derived suppressor cells accumulation in ovarian cancer and delays tumor growth

Cited by 16 publications

References 41 publications

Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia

Establishment and validation of a carbohydrate metabolism-related gene signature for prognostic model and immune response in acute myeloid leukemia

Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy

Friend and foe: the regulation network of ascites components in ovarian cancer progression

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