p16 methylation is a potential predictive marker for abemaciclib sensitivity in gastric cancer

Bae, Hyun Cheol; Kang, Sun Kyoung; Kwon, Woo Sun; Jeong, Inhye; Park, Sejung; Kim, Tae Soo; Kim, Kyoo Hyun; Kim, Hyunki; Jeong, Hei Cheul; Chung, Hyun Cheol; Rha, Sun Young

doi:10.1016/j.bcp.2020.114320

Cited by 12 publications

(8 citation statements)

References 39 publications

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“…Cell cycle control is often disrupted in GC, making it an attractive therapeutic target [ 8 ]. Notably, CDKN2A-CDK4/CDK6/CCND1 axis was affected recurrently: CDKN2A silencing was found in 35% of GC patients, CDK6 amplification was observed in 9% of GC patients and CCND1 amplification in 7% [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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Background Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors. Methods Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models. Results We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models. Conclusion This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.

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Section: Introductionmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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“…The p16 gene is an inhibitor of CDK4 and CDK6 kinases, which control cell cycle G1 progression, regulates G1-S cell cycle transition by phosphorylation of Rb signaling modulates the activation of CDK4, CDK6, and cyclin D1 as well as the release of E2F to drive cell cycle progression (2,5). In addition, homozygous p16 deletion or silencing via epigenetic methylation is often observed in GC (11), and the inactivation of p16 has been implicated in gastric carcinogenesis (12). According to this study, there was significant p16 methylation in dysplasia, intestinal metaplasia, and GC compared to non-neoplastic tissue, implicating the methylation of p16 promoter as a risk factor of GC, which was consistent with a recent study (13).…”

Section: Discussionmentioning

confidence: 99%

Association between eight hypermethylation-related genes and gastric cancer: a systematic review and meta-analysis

Ma¹,

Wang²,

Pu³

et al. 2022

Transl Cancer Res TCR

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Background: Although multiple gene promoter hypermethylation has been associated with gastric carcinogenesis, data on their specific relationship remains scant. We aimed to investigate the correlation between the status of multiple gene promoter methylation and gastric cancer (GC).Methods: We searched Pubmed, EMBASE, CNKI, Wanfang, Cqvip and Cochrane Library up to May 2021. We systematically assessed the association between methylation status of the CpG islands and the risk of GC. We compared the incidence of DNA methylation between tumor and non-tumor tissues, and evaluated the clinicopathological significance of the DNA methylation in gastric carcinoma. The data was presented by an odds ratio (OR) with an accompanying 95% confidence interval (CI). We then generated forest plots calculated by fixed-effects or random-effects model.Results: This study enrolled a total of 201 studies (140 papers). Our analysis showed a higher frequency of methylation of the CpG islands in GC tissues compared to non-neoplastic tissues. Besides, the data demonstrated that polygene's aberrant promoter methylation might be linked to the initial development and progression of GC.Discussion: The genes with altered DNA methylation might serve as epigenetic biomarkers, providing a promising molecular diagnostic and prognostic tool for human GC. However, our findings need further evaluation in large randomized controlled trials.

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“…Studies showed that high levels of cyclin E protein in GC correspond to increased resistance to palbociclib ( 169 ). The methylation of p16 increased the sensitivity of GC cells to abemaciclib, suggesting that abemaciclib is more effective in patients with hypermethylated p16 ( 170 ). Targeted therapies with a single drug are likely to develop drug resistance, but combinations of drugs are more effective in controlling the disease.…”

Section: Potential Therapeutic Targets Of the Rb-e2f Pathway In Gastric Cancermentioning

confidence: 99%

“…H. pylori infection can also change the epigenetics of cells, such as increased p16 methylation ( 179 ). In this regard, H. pylori -infected GC patients may be more sensitive to abemaciclib ( 170 ).…”

Section: Potential Therapeutic Targets Of the Rb-e2f Pathway In Gastric Cancermentioning

confidence: 99%

The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer

2021

Front. Oncol.

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Gastric cancer is the most common malignant tumor in the digestive tract, with very high morbidity and mortality in developing countries. The pathogenesis of gastric cancer is a complex biological process mediated by abnormal regulation of proto-oncogenes and tumor suppressor genes. Although there have been some in-depth studies on gastric cancer at the molecular level, the specific mechanism has not been fully elucidated. RB family proteins (including RB, p130, and p107) are involved in cell cycle regulation, a process that largely depends on members of the E2F gene family that encode transcriptional activators and repressors. In gastric cancer, inactivation of the RB-E2F pathway serves as a core transcriptional mechanism that drives cell cycle progression, and is regulated by cyclins, cyclin-dependent kinases, cyclin-dependent kinase inhibitors, p53, Helicobacter pylori and some other upstream molecules. The E2F proteins are encoded by eight genes (i.e. E2F1 to E2F8), each of which may play a specific role in gastric cancer. Interestingly, a single E2F such as E2F1 can activate or repress transcription, and enhance or inhibit cell proliferation, depending on the cell environment. Thus, the function of the E2F transcription factor family is very complex and needs further exploration. Importantly, the presence of H. pylori in stomach mucosa may affect the RB and p53 tumor suppressor systems, thereby promoting the occurrence of gastric cancer. This review aims to summarize recent research progress on important roles of the complex RB-E2F signaling network in the development and effective treatment of gastric cancer.

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p16 methylation is a potential predictive marker for abemaciclib sensitivity in gastric cancer

Cited by 12 publications

References 39 publications

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Association between eight hypermethylation-related genes and gastric cancer: a systematic review and meta-analysis

The Role and Clinical Implications of the Retinoblastoma (RB)-E2F Pathway in Gastric Cancer

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