CDK4/6 inhibitors in HR-positive breast cancer immunotherapy DOI Creative Commons
Minqian Shen, Zhiyuan Ma, Jiaxing Zhu

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 154, P. 108095 - 108095

Published: Dec. 25, 2024

Breast cancer is the most prevalent malignant tumour among women. Approximately 70 % of patients are hormone receptor (HR)-positive and undergo endocrine therapy as main form treatment; however, efficacy this type limited by some factors, such drug resistance complex microenvironments. Using network pharmacology molecular docking, study examined how CDK4/6 inhibitors enhance effects immunotherapy for HR-positive breast cancer, focusing on their microenvironment (TME) immune cell activity. inhibitor influence crucial signalling pathways, including TP53 EGFR, underscoring importance in modulating responses combating resistance. Our analysis revealed that combination with other immunotherapies, checkpoint inhibitors, might play an important role improving effectiveness treatment cancer. This provides new perspectives options cancers, promoting ongoing research improvements therapeutic approaches.

Language: Английский

Identification of the novel exhausted T cell CD8 + markers in breast cancer DOI Creative Commons
Hengrui Liu,

Angela Dong,

Ayana Meegol Rasteh

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 19, 2024

Cancer is one of the most concerning public health issues and breast cancer common cancers in world. The immune cells within tumor microenvironment regulate development. In this study, single cell data sets were used to identify marker gene for exhausted CD8 + T (CD8Tex) cancer. Machine learning methods cluster subtypes establish prognostic models with bulk using evaluate impacts CD8Tex. We analyzed overexpressing survival-associated genes identified CD8Tex hub protein-protein-interaction network. relevance T-cells was evaluated. clinical associations sequencing spatial data. pan-cancer expression, survival, association analyzed. biomarker CD8Tex-based subtyping systems performed well separation patients different survival. CRTAM, CLEC2D, KLRB1 as demonstrated have potential therapy impact. This study provides a unique view critical therapy.

Language: Английский

Citations

42
Harnessing the tumor microenvironment: targeted cancer therapies through modulation of epithelial-mesenchymal transition DOI Creative Commons
Antonino Glaviano,

Hannah Lau,

Lukas M. Carter

et al.

Journal of Hematology & Oncology, Journal Year: 2025, Volume and Issue: 18(1)

Published: Jan. 13, 2025

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, signaling molecules that interact promote growth therapeutic resistance. Elucidating the intricate interactions between cells TME crucial in understanding progression challenges. A critical process induced by epithelial-mesenchymal transition (EMT), wherein epithelial acquire mesenchymal traits, which enhance their motility invasiveness progression. By targeting various components TME, novel investigational strategies aim disrupt TME's contribution EMT, thereby improving efficacy, addressing resistance, offering a nuanced approach therapy. This review scrutinizes key players emphasizing avenues therapeutically components. Moreover, article discusses implications for resistance mechanisms highlights current toward modulation along with potential caveats.

Language: Английский

Citations

12
Molecular principles underlying aggressive cancers DOI Creative Commons
Ruth Nussinov, Bengi Ruken Yavuz, Hyunbum Jang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 16, 2025

Language: Английский

Citations

3
Pan-cancer analysis and single-cell analysis identifies the CENPN as a biomarker for survival prognosis and immunotherapy DOI Creative Commons

Nie Zhang,

Zhuoying He,

Xuejin Qin

et al.

Discover Oncology, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 17, 2025

Language: Английский

Citations

0
Targeted degradation of CDK4/6 by LA-CB1 inhibits EMT and suppresses tumor growth in orthotopic breast cancer DOI Creative Commons
Jingliang He, Shunfang Liu, Siyi Zhang

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 4, 2025

Cyclin-dependent kinases 4 and 6 (CDK4/6) are central regulators of cell cycle progression frequently dysregulated in cancers, including breast cancer. While selective CDK4/6 inhibitors like Palbociclib, Ribociclib, Abemaciclib have shown clinical benefit hormone receptor-positive (HR+) cancer, their efficacy is often limited by resistance mechanisms dose-limiting toxicities. In this study, we developed LA-CB1, a novel derivative that induces degradation through the ubiquitin-proteasome pathway, aiming to achieve sustained inhibition CDK4/6-Rb axis. LA-CB1 demonstrated potent anti-proliferative effects various cancer lines, with notable triple-negative (TNBC) HR + models. Molecular docking studies confirmed high-affinity binding ATP-binding pocket CDK4/6. Mechanistic revealed G0/G1 arrest promotes apoptosis Importantly, also suppressed epithelial-mesenchymal transition (EMT), inhibiting key processes such as migration, invasion, angiogenesis, indicating its ability disrupt multiple hallmarks an orthotopic model, significantly reduced tumor growth dose-dependent manner. These results suggest represents promising therapeutic strategy targeting for degradation, addressing limitations associated current inhibitors, providing broad anti-tumor activity aggressive types TNBC.

Language: Английский

Citations

0
Distinct allosteric networks in CDK4 and CDK6 in the cell cycle and in drug resistance DOI Creative Commons
Wengang Zhang,

D. Michael Bradburn,

Gretchen Heidebrink

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Abstract Cyclin-dependent kinases 4 and 6 (CDK4 CDK6) are key regulators of the G1-S phase transition in cell cycle. In cancer cells, CDK6 overexpression often outcompetes CDK4 driving cycle progression, contributing to resistance against CDK4/6 inhibitors (CDK4/6i). This suggests distinct functional conformational differences between these two kinases, despite their striking structural sequence similarities. Understanding mechanisms that differentiate is crucial, as CDK4/6i—frequently linked overexpression—remains a significant therapeutic challenge. Notably, upregulated CDK4/6i-resistant cancers rapidly proliferating hematopoietic stem underscoring its unique regulatory roles. We hypothesize dynamics explain phosphorylation retinoblastoma protein, Rb, inhibitor efficacy, control. leads us question how dissimilar encode actions . To elucidate differential activities, molecular mechanisms, binding, we combine biochemical assays (MD) simulations. discover have allosteric networks connecting β3-αC loop G-loop. exhibits stronger coupling shorter path lengths regions, resulting higher kinase activity upon cyclin binding impacting specificity. also an unrecognized role unstructured C-terminus, which allosterically connects stabilizes R-spine, facilitating slightly activity. Our findings bridge gap similarity divergence CDK6, advancing understanding regulation biology. Graphical abstract

Language: Английский

Citations

0
Distinct allosteric networks in CDK4 and CDK6 in the cell cycle and in drug resistance DOI
Wengang Zhang,

D. Michael Bradburn,

Gretchen Heidebrink

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169121 - 169121

Published: March 1, 2025

Language: Английский

Citations

0
Integrative analysis of m6A-SNPs and single-cell RNA sequencing reveals key drivers of endocrine combined with CDK4/6 inhibitor therapy resistance in ER+ breast cancer DOI Creative Commons

Ruijie Ming,

Han Zhang, Huan Wu

et al.

Frontiers in Pharmacology, Journal Year: 2025, Volume and Issue: 16

Published: April 15, 2025

Background Endocrine therapy combined with CDK4/6 inhibitors remains a standard treatment for ER+ breast cancer, yet resistance is prevalent challenge. This study explores the role of N6-methyladenosine (m6A) modifications, influenced by m6A-SNPs, in shaping resistance, utilizing single-cell RNA sequencing to delineate underlying molecular mechanisms. Methods We integrated genome-wide association data transcriptomic profiles from cancer patients, focusing on differences between resistant and sensitive responses inhibitors. m6A-SNPs were identified analyzed their impact gene expression interactions RNA-binding proteins, particular focus roles within key cellular pathways. Results The crucial associated resistance. Notably, changes FILIP1L TOM1L1, related these SNPs, mapped using pseudotime trajectory analysis, which traced evolution states. TOM1L1 exhibited dynamic along trajectory, correlating significant shifts cell fate decisions. These findings underscore potential as mediators development particularly through involvement PI3K-Akt Wnt signaling pathways, critical progression drug Conclusion Our emphasize importance influencing cancer. regulation developmental tumor cells sensitivity provides insights into complexity results pave way developing targeted therapies that modify m6A-driven offering new strategies counteract improve patient outcomes.

Language: Английский

Citations

0
Anticancer Potential of Prebiotics: Targeting Estrogen Receptors and PI3K/AKT/mTOR in Breast Cancer DOI Creative Commons
Hussein Sabit,

Sama Abouelnour,

Bassel M. Hassen

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(4), P. 990 - 990

Published: April 18, 2025

Estrogen receptors (ERs) play a critical role in breast cancer (BC) development and progression, with ERα being oncogenic ERβ exhibiting tumor-suppressive properties. The interaction between ER signaling other molecular pathways, such as PI3K/AKT/mTOR, influences tumor growth endocrine resistance. Emerging research highlights the of prebiotics modulating gut microbiota, which may influence estrogen metabolism, immune function, therapeutic responses BC. This review explores impact on receptor modulation, microbiota composition, regulation, metabolic pathways cancer. potential adjunctive therapies to enhance treatment efficacy mitigate chemotherapy-related side effects is discussed. A comprehensive analysis recent preclinical clinical studies was conducted, examining reprogramming short-chain fatty acids (SCFAs) derived from prebiotic fermentation epigenetic regulation resistance also evaluated. Prebiotics were found modulate microbiota-estrogen axis, reduce inflammation, responses. SCFAs demonstrated selective downregulation reprogramming, suppressing growth. Synbiotic interventions effects, improving quality life patients. offer promising avenue for prevention therapy by pathways. Future trials are needed validate their treatments management.

Language: Английский

Citations

0
CELL CYCLE DYSREGULATION IN CANCER DOI
Antonino Glaviano, Samarendra Kumar Singh, E. Hui Clarissa Lee

et al.

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 77(2), P. 100030 - 100030

Published: Dec. 24, 2024

Cancer is a systemic manifestation of aberrant cell cycle activity and dysregulated growth. Genetic mutations can determine tumor onset by either augmenting division rates or restraining normal controls such as arrest apoptosis. As result, cells not only undergo uncontrolled but also become compromised in their ability to exit the accurately. Regulation progression enabled specific surveillance mechanisms known checkpoints, aberrations these signaling pathways often culminate cancer. For instance, DNA damage which preclude generation augmentation G1, S, G2 phases, are defective cancer cells, allowing spite accumulation genetic errors. Notably, tumors have evolved dependent on checkpoints for survival. example, checkpoint replication stress mitotic rarely remain intact because any could result irreparable catastrophic chromosomal missegregation leading death. In this review, we initially focus control functions involved then proceed examine how provide new therapeutic windows that be exploited therapy. SIGNIFICANCE STATEMENT: Conversely, missegregation, This review focuses an emerging understanding opportunities

Language: Английский

Citations

2