Development of an Oncogenic Driver Alteration Associated Immune-Related Prognostic Model for Stage I-II Lung Adenocarcinoma DOI Creative Commons
Jianzhao Xu, Gong Chen, Zheng-Fu Xie

et al.

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 10

Published: Jan. 28, 2021

Lung adenocarcinoma (LUAD) needs to be stratified for its heterogeneity. Oncogenic driver alterations such as EGFR mutation, ALK translocation, ROS1 and BRAF mutation predict response treatment LUAD. Since oncogenic may modulate immune in tumor microenvironment that influence prognosis LUAD, the effects of , on remain unclear. Immune-related prognostic model associated with is needed. In this study, we performed Cox-proportional Hazards Analysis based L1-penalized (LASSO) establish an immune-related (IPM) stage I-II LUAD patients, which was 3 genes ( PDE4B RIPK2 IFITM1 ) significantly enriched patients without The Cancer Genome Atlas (TCGA) database. Then, were categorized into high-risk low-risk groups individually according IPM defined risk score. predicting ability validated GSE31210 GSE26939 downloaded from Gene Expression Omnibus (GEO) High-risk lower overall survival (OS) rates independent cohorts (all P < 0.05). Moreover, independently predicted OS TCGA cohort = 0.011). group had higher proportions macrophages M1 activated mast cells but memory B cells, resting CD4 T than addition, a expression CTLA-4 PDCD1 HAVCR2 TIGIT summary, established novel could provide new biomarkers stratification patients.

Language: Английский

Targeted protein degradation of PDE4 shortforms by a novel proteolysis targeting chimera DOI Creative Commons
Yuan Yan Sin,

Aoife Giblin,

Aleksandra Judina

et al.

FEBS Journal, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 13, 2024

Cyclic AMP (cAMP) has a crucial role in many vital cellular processes and there been much effort expended the discovery of inhibitors against enzyme superfamily that degrades this second messenger, namely phosphodiesterases (PDEs). The journey competitive PDE to clinic hampered by side effects profiles have resulted from lack selectivity for subfamilies individual isoforms because high conservation catalytic site sequences structures. Here we introduce proteolysis targeting chimera (PROTAC) can specifically target small subset PDE4 family send degradation at proteasome recruiting ubiquitin E3 ligase into proximity with PDE. We constructed our PROTAC (KTX207) using previously characterized inhibitor, show evolution compound improves selectivity, potency enables long‐lasting effect even after is removed cells short treatment duration. Functionally, KTX207 more effective increasing cAMP, 100 times anti‐inflammatory, significantly better reducing growth cancer cell models than inhibitor alone. Our study highlights advantages targeted versus active‐site occupancy inhibition discusses potential novel pharmacological approach improve safety profile future.

Language: Английский

Citations

2
Discovery of novel trimethoxyphenylbenzo[d]oxazoles as dual tubulin/PDE4 inhibitors capable of inducing apoptosis at G2/M phase arrest in glioma and lung cancer cells DOI
Jie Liu, Ye Wan, Jiangping Xu

et al.

European Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 224, P. 113700 - 113700

Published: July 15, 2021

Language: Английский

Citations

13
Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia DOI Creative Commons
Qi Li,

Yujing Cheng,

Wanlu Chen

et al.

Open Medicine, Journal Year: 2023, Volume and Issue: 18(1)

Published: Jan. 1, 2023

Abstract Phosphodiesterase 4D interacting protein ( PDE4DIP ) interacts with cAMP-specific phosphodiesterase and its abnormal expression promotes the development of hematological malignancies, breast cancer, pineal cell carcinoma. However, there is currently no systematic pan-cancer analysis association between various cancers. Thus, this study aimed to elucidate potential functions in Based on multiple public databases online websites, we conducted comprehensive analyses for cancers, including differential expression, prognosis, genetic variation, DNA methylation, immunity. We thoroughly analyzed specific role acute myeloid leukemia (LAML). The results indicated that were differences kidney chromophobe, LAML, pheochromocytoma paraganglioma, thymoma, uveal melanoma, had prognostic value. was also correlated immune infiltration, immune-related genes Functional enrichment showed mainly related pathways immunoglobulin complexes, T-cell receptor response regulatory signaling pathways. Our systematically revealed first time immunotherapeutic value LAML.

Language: Английский

Citations

5
Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer DOI Creative Commons
Özge Saatci, Metin Çetįn, Meral Üner

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 2, 2023

Abstract Resistance to endocrine therapy and CDK4/6 inhibitors, the standard of care (SOC) in estrogen receptor-positive (ER+) breast cancer, greatly reduces patient survival. Therefore, elucidating mechanisms sensitivity resistance SOC identifying actionable targets are urgently needed. Here, we show that causes DNA damage toxic PARP1 trapping upon generation a functional BRCAness (i.e., BRCA1/2 deficiency) phenotype, leading increased histone parylation reduced H3K9 acetylation, resulting transcriptional blockage cell death. Mechanistically, downregulates phosphodiesterase 4D (PDE4D), novel ER target gene feedforward loop with ER, cAMP, PKA-dependent phosphorylation mitochondrial COXIV-I, ROS damage. However, during resistance, an ER-to-EGFR switch induces PDE4D overexpression via c-Jun. Notably, combining inhibitors PDE4D, EGFR or overcomes irrespective status, providing for restoring efficacy.

Language: Английский

Citations

5
Development of an Oncogenic Driver Alteration Associated Immune-Related Prognostic Model for Stage I-II Lung Adenocarcinoma DOI Creative Commons
Jianzhao Xu, Gong Chen, Zheng-Fu Xie

et al.

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 10

Published: Jan. 28, 2021

Lung adenocarcinoma (LUAD) needs to be stratified for its heterogeneity. Oncogenic driver alterations such as EGFR mutation, ALK translocation, ROS1 and BRAF mutation predict response treatment LUAD. Since oncogenic may modulate immune in tumor microenvironment that influence prognosis LUAD, the effects of , on remain unclear. Immune-related prognostic model associated with is needed. In this study, we performed Cox-proportional Hazards Analysis based L1-penalized (LASSO) establish an immune-related (IPM) stage I-II LUAD patients, which was 3 genes ( PDE4B RIPK2 IFITM1 ) significantly enriched patients without The Cancer Genome Atlas (TCGA) database. Then, were categorized into high-risk low-risk groups individually according IPM defined risk score. predicting ability validated GSE31210 GSE26939 downloaded from Gene Expression Omnibus (GEO) High-risk lower overall survival (OS) rates independent cohorts (all P < 0.05). Moreover, independently predicted OS TCGA cohort = 0.011). group had higher proportions macrophages M1 activated mast cells but memory B cells, resting CD4 T than addition, a expression CTLA-4 PDCD1 HAVCR2 TIGIT summary, established novel could provide new biomarkers stratification patients.

Language: Английский

Citations

12