PI3Kα inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment

Shi, Jinqiao; Xing, Hui; Wang, Yu-xiang; Zhang, Xi; Zhan, Qimin; Geng, Meiyu; Ding, Jian; Meng, Linghua

doi:10.1016/j.canlet.2019.05.040

Cited by 28 publications

(28 citation statements)

References 32 publications

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“…Our previous studies demonstrated that CYH33 significantly inhibited the proliferation of a panel of human breast cancer cells and non-small cell lung cancer cells by the induction of G 1 phase arrest. 20 24 Notably, we found that CYH33 enhanced the activity of radiation against esophageal squamous cell carcinoma by abrogating the radiation-induced phosphorylation of AKT and infiltration of M2-like macrophages, 21 indicating its potential effect on the TME.…”

Section: Introductionmentioning

confidence: 79%

“…We previously reported that CYH33 overcame TAM-mediated resistance to radiation therapy, suggesting that CYH33 may execute its activity by reshaping the TME. 21 To evaluate the antitumor activity of CYH33 in an immune-competent context, three lines of murine triple-negative breast cancer cells were used, namely 4T1, PY8119, and EMT6. As shown in figure 1A , CYH33 and alpelisib showed little activity against the proliferation of 4T1 cells with a GI 50 over 10 µM.…”

Section: Resultsmentioning

confidence: 99%

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PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8⁺T cells and promoting fatty acid metabolism

Sun

Zhang

Wang

et al. 2021

J Immunother Cancer

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BackgroundThe phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer and plays important roles in both malignant and immune cells. The effect of PI3Kα inhibitors on the tumor microenvironment (TME) remains largely unknown. Here, we investigated the modulation of the TME by a clinical PI3Kα-specific inhibitor CYH33.MethodsThe activity of CYH33 against a panel of murine tumors in the immune-competent context or athymic mice was detected. Single-cell RNA sequencing and multi-parameter flow cytometry were performed to determine the immune profiling of TME. The effect of CYH33 on immune cells was conducted with primary murine cells.ResultsCYH33 exhibited more potent antitumor activity in immune-competent context. CYH33 enhanced the infiltration and activation of CD8+T and CD4+T cells, while attenuating M2-like macrophages and regulatory CD4+T cells. Increase in memory T cells was confirmed by the induction of long-term immune memory on CYH33 treatment. Mechanistically, CYH33 relieved the suppressed expansion of CD8+T cells via preferential polarization of the macrophages to the M1 phenotype. CYH33 promoted fatty acid (FA) metabolism in the TME, while FA enhanced the activity of CD8+T cells in vitro. The combination of CYH33 with the FA synthase (FASN) inhibitor C75 synergistically inhibited tumor growth with enhanced host immunity.ConclusionsCYH33 induces immune activation and synergizes with FASN inhibitor to further promote the antitumor immunity, which gains novel insights into how PI3K inhibitors exert their activity by modulating TME and provides a rationale for the concurrent targeting of PI3K and FASN in breast cancer treatment.

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Section: Introductionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8⁺T cells and promoting fatty acid metabolism

Sun

Zhang

Wang

et al. 2021

J Immunother Cancer

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“…The strategies that target the PI3K/AKT pathway help to inhibit cadherin switching, diminish cell proliferation and migration, alleviate inflammation, restore chemosensitivity, and increase radiosensitivity in EC cells. For instance, the combination of a clinical PI3Kα-selective inhibitor CYH33 and radiation promoted DNA damage, cell cycle arrest and apoptosis in ESCC cells [ 132 ]. In the PDX model, CYH33 and radiation inhibited tumor growth, lowered Akt phosphorylation and M2-like macrophage infiltration [ 132 ].…”

Section: Application Of Pdx Models In Evaluating Therapeutic Targets For Chemotherapymentioning

confidence: 99%

“…For instance, the combination of a clinical PI3Kα-selective inhibitor CYH33 and radiation promoted DNA damage, cell cycle arrest and apoptosis in ESCC cells [ 132 ]. In the PDX model, CYH33 and radiation inhibited tumor growth, lowered Akt phosphorylation and M2-like macrophage infiltration [ 132 ]. Oridonin, Xanthohumol, and Scutellarin are natural compounds isolated from herbs.…”

Section: Application Of Pdx Models In Evaluating Therapeutic Targets For Chemotherapymentioning

confidence: 99%

Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

Lan

Xue

Dunmall

et al. 2021

Aging

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Esophageal cancer (EC) represents a human malignancy, diagnosed often at the advanced stage of cancer and resulting in high morbidity and mortality. The development of precision medicine allows for the identification of more personalized therapeutic strategies to improve cancer treatment. By implanting primary cancer tissues into immunodeficient mice for expansion, patient-derived xenograft (PDX) models largely maintain similar histological and genetic representations naturally found in patients’ tumor cells. PDX models of EC (EC-PDX) provide fine platforms to investigate the tumor microenvironment, tumor genomic heterogeneity, and tumor response to chemoradiotherapy, which are necessary for new drug discovery to combat EC in addition to optimization of current therapeutic strategies for EC. In this review, we summarize the methods used for establishing EC-PDX models and investigate the utilities of EC-PDX in screening predictive biomarkers and potential therapeutic targets. The challenge of this promising research tool is also discussed.

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“…Recent advances demonstrated that understanding the molecular mechanisms of malignant development and progression is very important for the development of novel targeted therapeutic agents for the treatment of human cancer (6). However, up to now, ESCC is still one of the least studied malignancies in the world, and the critical signaling pathways and molecular mechanisms involved in the initiation, development and progression of ESCC are not fully elucidated (7). Therefore, there is an urgent need to identify the potential molecules involved in ESCC tumorigenesis and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma

Chen

Wei

et al. 2020

Front. Oncol.

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Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignancy and is one of the most important cause of cancer related mortalities in the world. However, there is no clinically effective targeted therapeutic drugs for ESCC due to lack of valuable molecular therapeutic targets. In the present study, we investigated the biological function and molecular mechanisms of maternal embryonic leucine zipper kinase (MELK) in ESCC. The expression of MELK mRNA and protein was determined in cell lines and clinical samples of ESCC. MTT, focus formation and soft agar assays were carried out to measure cell proliferation and colony formation. Wound healing and transwell assays were used to assess the capacity of tumor cell migration and invasion. Nude mice models of subcutaneous tumor growth and lung metastasis were performed to examine the function of MELK in tumorigenecity and metastasis of ESCC cells. High expression of MELK was observed in ESCC cell line and human samples, especially in the metastatic tumor tissues. Moreover, overexpression of MELK promoted cell proliferation, colony formation, migration and invasion, and increased the expression and enzyme activity of MMP-2 and MMP-9 in ESCC cells. More importantly, enhanced expression of MELK greatly accelerated tumor growth and lung metastasis of ESCC cells in vivo. In contrast, knockdown of MELK by lentiviral shRNA resulted in an opposite effect both in vitro and in animal models. Mechanistically, MELK facilitated the phosphorylation of FOXM1, leading to activation of its downstream targets (PLK1, Cyclin B1, and Aurora B), and thereby promoted tumorigenesis and metastasis of ESCC cells. In conclusion, MELK enhances tumorigenesis, migration, invasion and metastasis of ESCC cells via activation of FOXM1 signaling pathway, suggesting MELK is a potential therapeutic target for ESCC patients, even those in an advanced stage.

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PI3Kα inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment

Cited by 28 publications

References 32 publications

PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8⁺T cells and promoting fatty acid metabolism

PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8⁺T cells and promoting fatty acid metabolism

Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma

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PI3Kα inhibitors sensitize esophageal squamous cell carcinoma to radiation by abrogating survival signals in tumor cells and tumor microenvironment

Cited by 28 publications

References 32 publications

PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8+T cells and promoting fatty acid metabolism

PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8+T cells and promoting fatty acid metabolism

Patient-derived xenograft: a developing tool for screening biomarkers and potential therapeutic targets for human esophageal cancers

Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma

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PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8⁺T cells and promoting fatty acid metabolism

PI3Kα inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8⁺T cells and promoting fatty acid metabolism