The antitumor activity of osimertinib plus palbociclib in non-small cell lung cancer patient-derived xenograft (PDX)/2D/3D culture models harboring EGFR amplification and CDKN2A/2B homozygous deletions DOI
Jen‐Fen Fu,

Cheng‐Lung Hsu,

Ping‐Chih Hsu

et al.

Neoplasia, Journal Year: 2024, Volume and Issue: 57, P. 101039 - 101039

Published: Aug. 14, 2024

Non-small cell lung cancer (NSCLC) patients without targetable driver mutation have limited treatment options. In this study, we aimed to explore a new therapeutic strategy by using established nine patient-derived xenograft (PDX) and two-dimensional (2D) /3D culture models with specific genetic alternations. The gene mutations copy number aberrations were detected next-generation sequencing confirmed polymerase chain reaction (PCR) followed DNA sequencing, genomic quantitative PCR. Protein expression was evaluated immunohistochemistry. Drug sensitivities of PDX/2D/3D in vivo vitro antitumor assays. RNA interference performed silence expression. Our study found that 44.4 % (4/9) cases had CDKN2A homozygous deletion (homdel), while 33.3 (3/9) CDKN2B homdel. Additionally, 22.2 (2/9) amplification (amp) wildtype CDK4, CDK6, EGFR. Among the cases, 77.8 (7/9) lacked CDKN2A, high EGFR protein Moreover, KRAS mutations, 66.7 (6/9) TP53 mutations. Antitumor activity osimertinib plus palbociclib assessed four models, two which simultaneous amp CDKN2A/2B data showed NSCLC homdel sensitive combined drugs. Additional oncogenic reduced drug's effect. is responsible for sensitivity. Osimertinib effectively treat CDK6 absence mutation.

Language: Английский

Targeting CDK4/6 suppresses colorectal cancer by destabilizing YAP1 DOI Creative Commons

Yalei Wen,

Xiao Yang,

Shengrong Li

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(3)

Published: Feb. 17, 2025

Abstract Colorectal cancer (CRC) is among the most prevalent and deadly cancers worldwide. The Yes‐associated protein 1 (YAP1) frequently dysregulated in cancers, contributing to stemness, chemoresistance, cancer‐related death. However, strategies directly targeting YAP1 have not yet been successful because of lack active binding pockets unregulated toxicity. In this study, our Food Drug Administration (FDA)‐approved drug screening reveals that abemaciclib, a cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor, dramatically promotes proteasome‐dependent degradation YAP1, thereby inhibiting tumor progression CRC cells patient‐derived xenograft models. We further identify deubiquitinating enzyme 3 (DUB3) as bona fide deubiquitinase CRC. Mechanistically, CDK4/6 phosphorylates DUB3 at Ser41, activating deubiquitinate stabilize YAP1. Conversely, loss Ser41 phosphorylation by inhibition or Ser41A mutation, suppresses YAP1‐driven progression. Histological analysis shows positive correlation between expression specimens. Collectively, study uncovers novel oncogenic role CDK4/6‐DUB3 pathway, which stabilization tumor‐promoting function, highlighting offers potential therapeutic strategy for with aberrantly upregulated

Language: Английский

Citations

1
Gut microbiota as a biomarker and modulator of anti-tumor immunotherapy outcomes DOI Creative Commons

Jiexi Yan,

Lu Yang,

Qingmiao Ren

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 28, 2024

Although immune-checkpoint inhibitors (ICIs) have significantly improved cancer treatment, their effectiveness is limited by primary or acquired resistance in many patients. The gut microbiota, through its production of metabolites and regulation immune cell functions, plays a vital role maintaining balance influencing the response to immunotherapies. This review highlights evidence linking specific microbial characteristics increased therapeutic efficacy variety cancers, such as gastrointestinal melanoma, lung cancer, urinary system reproductive suggesting microbiota’s potential predictive biomarker for ICI responsiveness. It also explores possibility enhancing fecal microbiota transplantation, probiotics, prebiotics, synbiotics, postbiotics, dietary modifications. Moreover, underscores need extensive randomized controlled trials confirm value establish guidelines microbiota-targeted interventions immunotherapy. In summary, article suggests that balanced key maximizing immunotherapy benefits calls further research optimize modulation strategies treatment. advocates deeper comprehension complex interactions between host immunity, therapy, aiming more personalized effective treatment options.

Language: Английский

Citations

6
Evaluating patients on CDK-4/6 inhibitor treatment for differences in treatment according to demographic variables DOI

Sneha Rajendran,

Marina Petruzzi,

Dianxu Ren

et al.

Future Oncology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 4

Published: Jan. 26, 2025

The accessibility and outcomes of cyclin-dependent kinase 4 6 inhibitors (CDKi) in metastatic breast cancer (MBC) according to demographic factors are unknown. Retrospective review patients with ER+ MBC prescribed first-line CDKi therapy from January 2015 through December 2022. Abstraction included time prescription drug initiation (TTI), progression (TTP), death or 6/30/2022, variables (age, race, partner status, insurance type, BMI, number comorbidities). Descriptive, comparative, correlational statistics used. N = 173 patients. No significant differences TTI TTP. In the multivariate model death, Medicaid had significantly shorter overall survival than private insurance. is associated worse therapy, not attributed delay. Personalization support may be helpful.

Language: Английский

Citations

0
Overexpression or knockdown of the P2X7 receptor regulates the progression of non-small cell lung cancer, involving GSK-3β and JNK signaling pathways DOI

Qingqing Yu,

Xiaoxiang Peng, Geng Xu

et al.

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: 995, P. 177421 - 177421

Published: Feb. 22, 2025

Language: Английский

Citations

0
Design, synthesis and evaluation of acetylcholine-antitumor lipids hybrids lead to identification of a potential anticancer agent disrupting CDK4/6-Rb pathway in lung cancer DOI Creative Commons
Ahmed H.E. Hassan,

Eun Seo Bae,

Youngdo Jeong

et al.

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Hybridization of acetylcholine with antitumor lipids (ATLs) was explored to achieve novel potential anticancer agents.

Language: Английский

Citations

0
Recent Developments in Targeting the Cell Cycle in Melanoma DOI Open Access
Christie Hung, Trang Nguyen, Poulikos I. Poulikakos

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(8), P. 1291 - 1291

Published: April 11, 2025

Melanoma is an aggressive cancer with rising incidence, particularly among older individuals. Despite advancements in targeted therapies for BRAF and MEK proteins immunotherapies, many patients either fail to respond or develop resistance. For those progressing on immunotherapy, limited treatment options remain. The Cyclin D–CDK4/6–RB pathway commonly dysregulated melanoma, up 90% of cases showing alterations that activate it. Although targeting Cyclin–CDK complexes has shown promise preclinical models, clinical responses have been suboptimal. This review explores the molecular mechanisms behind dysregulation melanoma challenges this pathway. It also discusses strategies improve efficacy CDK4/6 inhibitors, including combination overcome resistance enhance patient outcomes. Understanding these can guide development more effective treatments melanoma.

Language: Английский

Citations

0
Rationally Designed Pyrazolo[1,5-a]pyrimidines as Dual Inhibitors of CA IX/XII and CDK6: A Novel Approach for NSCLC Treatment DOI
Mahmoud S. Elkotamy,

Islam A. Elkelesh,

Simone Giovannuzzi

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 293, P. 117752 - 117752

Published: May 9, 2025

Language: Английский

Citations

0
Small cell lung cancer: emerging subtypes, signaling pathways, and therapeutic vulnerabilities DOI Creative Commons
Jing Zhang, Xiaoping Zeng,

Qiji Guo

et al.

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Aug. 5, 2024

Abstract Small cell lung cancer (SCLC) is a recalcitrant characterized by early metastasis, rapid tumor growth and poor prognosis. In recent decades, the epidemiology, initiation mutation characteristics of SCLC, as well abnormal signaling pathways contributing to its progression, have been widely studied. Despite extensive investigation, fewer drugs approved for SCLC. Recent advancements in multi-omics studies revealed diverse classifications SCLC that are featured distinct therapeutic vulnerabilities. With accumulation samples, different subtypes specific treatments these were further explored. The identification molecular has opened up novel avenues treatment SCLC; however, inconsistent uncertain classification hindered translation from basic research clinical applications. Therefore, comprehensives review essential conclude emerging related targeting vulnerabilities within pathways. this current review, we summarized risk factors, classification, We hope will facilitate subtyping theory application.

Language: Английский

Citations

2
Potential role of cyclin-dependent kinase 4/6 inhibitors in the treatment of mucosal melanoma DOI Creative Commons
Chaoji Shi, Houyu Ju, Yunteng Wu

et al.

Holistic Integrative Oncology, Journal Year: 2024, Volume and Issue: 3(1)

Published: May 28, 2024

Abstract Mucosal melanoma (MM) is a rare and aggressive form of with poorer prognosis compared to other subtypes. Recent large-scale next-generation sequencing studies, including our own research, have demonstrated that the molecular characteristics potential oncogenic drivers MM differ significantly from those cutaneous melanoma. The emergence selective CDK4/6 inhibitors, already approved for use in breast cancer undergoing phase III clinical trials solid tumors, represents promising development treatment MM. studies shown inhibitors not only induce cell cycle arrest but also play crucial role facilitating interaction between tumor cells host immune system. Moreover, findings indicate dysregulation progression due cyclin‐dependent kinase 4 (CDK4) amplification significant genetic characteristic substantial portion cases. Targeting CDK4 specific patients shows promise precision therapy, utilizing molecularly characterized patient-derived xenograft (PDX) models trials. This paper provides an overview existing literature on MM, as well preclinical investigations combination therapies treatment.

Language: Английский

Citations

1
A Novel Hybrid Model for Automatic Non-Small Cell Lung Cancer Classification Using Histopathological Images DOI Creative Commons
Oğuzhan KATAR, Özal Yıldırım, Ru San Tan

et al.

Diagnostics, Journal Year: 2024, Volume and Issue: 14(22), P. 2497 - 2497

Published: Nov. 8, 2024

: Despite recent advances in research, cancer remains a significant public health concern and leading cause of death. Among all types, lung is the most common cancer-related deaths, with cases linked to non-small cell (NSCLC). Accurate classification NSCLC subtypes essential for developing treatment strategies. Medical professionals regard tissue biopsy as gold standard identification subtypes. However, since images have very high resolutions, manual examination time-consuming depends on pathologist's expertise.

Language: Английский

Citations

1