SIRT5 participates in the suppressive tumor immune microenvironment of EGFR-mutant LUAD by regulating the succinylation of ACAT1

Heliyon, Год журнала: 2024, Номер 10(21), С. e39743 - e39743

Опубликована: Окт. 23, 2024

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) exhibits a poor response to immune checkpoint inhibitors (ICIs) by shaping suppressive tumor microenvironment (TIME), which characters as lacking cell infiltration; however, the underlying mechanism remains be elucidated. Here, we demonstrated that Sirtuin 5 (SIRT5), member of deacetylase SIRT family, functions desuccinylase acetyl-CoA acetyltransferase 1 (ACAT1) and enhances enzymatic activity ACAT1 activate NRF2 pathway, inhibiting secretion chemokines CCL5 CXCL10, are important for recruiting CD8

Язык: Английский

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RBM15 facilitates osimertinib resistance of lung adenocarcinoma through m6A-dependent epigenetic silencing of SPOCK1

Oncogene, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 11, 2024

Lung cancer is the leading cause of cancer-related mortality globally. N6-methyladenosine (m6A) most abundant modification in mammalian mRNA and involved biological regulation tumors, including lung cancer. However, role m6A-related proteins, such as RNA-binding motif protein 15 (RBM15), progression remains largely unknown. Our study indicated that RBM15 significantly overexpressed adenocarcinoma, serving an independent prognostic factor for poor outcomes facilitating tumor cell proliferation migration. was markedly elevated patients with EGFR mutations, correlating a poorer prognosis, while it had negligible value wild-type patients. As EGFR-tyrosine kinase inhibitors (TKIs) are standard treatment we subsequently determined drives osimertinib resistance via novel mechanism: enhancing m6A cwcv- kazal-like domains proteoglycan 1 (SPOCK1) mRNA, promoting epithelial-mesenchymal transition-mediated through bypass activation pathway. These findings were validated osimertinib-resistant H1975 cells organoids from adenocarcinoma. Furthermore, RBM15-SPOCK1 axis activated drug-tolerant persister cells, indicating early targeting during EGFR-TKI could dramatically extend patient response benefit TKI therapy. results emphasize critical reversing propose promising therapeutic target prolonging benefits

Язык: Английский

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Encouraging Fussy Eaters in EGFR-Mutated Lung Cancer

Journal of Thoracic Oncology, Год журнала: 2024, Номер 19(8), С. 1125 - 1127

Опубликована: Авг. 1, 2024

Язык: Английский

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Synthesis and Biological Evaluation of Novel Cationic Rhenium and Technetium-99m Complexes Bearing Quinazoline Derivative for Epidermal Growth Factor Receptor Targeting

Pharmaceutics, Год журнала: 2024, Номер 16(9), С. 1213 - 1213

Опубликована: Сен. 16, 2024

Background/Objectives: Epidermal growth factor receptor (EGFR) plays a vital role in cell proliferation and survival, with its overexpression linked to various malignancies, including non-small lung cancer (NSCLC). Although EGFR tyrosine kinase inhibitors (TKIs) are key therapeutic strategy, acquired resistance relapse remain challenges. This study aimed synthesize evaluate novel rhenium-based complexes incorporating TKIs enhance anticancer efficacy, particularly radiosensitization. Methods: We synthesized rhenium tricarbonyl complex (Complex 2) 99mTc analog 2’) by triphenylphosphine instead of bromine as the monodentate ligand PF6− counter-ion, resulting positively charged compound that forms cationic structures. Cytotoxicity inhibition were evaluated A431 cells overexpressing using MTT assays, Western blotting, flow cytometry. Radiosensitization was tested through clonogenic assays. The complex’s radiochemical yield, stability, lipophilicity also assessed. Results: Complex 2 exhibited significant cytotoxicity an IC50 2.6 μM phosphorylation 130.6 nM. Both 1 induced G0/G1 cycle arrest, causing apoptosis. observed at doses above Gy. 2’ demonstrated high stability favorable (LogD7.4 3.2), showing 12% cellular uptake after 30 min. Conclusions: Complexes show promise dual-function agents, offering inhibition, apoptosis induction, Their potential radiopharmaceuticals warrants further in-depth investigation preclinical models.

Язык: Английский

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Identification of expression profiles and transcription factors during EGFR‐TKI acquired resistance in LUAD

Precision Medical Sciences, Год журнала: 2024, Номер unknown

Опубликована: Окт. 10, 2024

Abstract Lung cancer is one of the most‐common malignant tumors while lung adenocarcinoma (LUAD) serves as major subtype cancer. The epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) are an important choice in LUAD targeted therapies. However, EGFR‐TKI acquired resistance always happens, urging for further investigating and overcoming. We scRNA‐seq data from GSE149383 PRJNA591860 databases. identified typical tendency during progression LUAD. Furthermore, we investigate potential expression profiles, upstream transcription factors, interacting drugs with LUAD, participating resistance. According to databases, was “decrease early raise later” Day 0 11. Seven pairs factors target genes were explored including TFDP1‐RPA3, TFDP1‐EIF2S1, TFDP1‐COTL1, TFDP1‐CBX1, MYBL2‐STMN1, EZH2‐CYCS, BRCA1‐STMN1. Several screened especially TANDUTINIB. recognized factor‐target gene resistance, which could provide a novel insight clinical treatments.

Язык: Английский

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