<i>P16</i> Methylation Leads to Paclitaxel Resistance of Advanced Non-Small Cell Lung Cancer

Liu, Zhaojun; Lin, Huann‐shyang; Gan, Ying; Cui, Chenghua; Zhang, Baozhen; Gu, Lin; Zhou, Jing; Zhu, Guangying; Deng, Dajun

doi:10.7150/jca.26482

Cited by 19 publications

(11 citation statements)

References 37 publications

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“…shorter treatment duration [12]. We recently reported that P16 methylation could increase the resistance of lung (and stomach) cancers to paclitaxel treatment in a clinical trial [41]. In contrast, here, we reveal that P16 methylation can increase the sensitivity of lung and stomach cancers to palbociclib.…”

Section: Discussioncontrasting

confidence: 67%

P16 methylation increases the sensitivity of cancer cells to the CDK4/6 inhibitor palbociclib

Zhang

et al. 2019

PLoS ONE

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The P16 (CDKN2Aink4a) gene is an endogenous CDK4/6 inhibitor. Palbociclib (PD0332991) is an anti-CDK4/6 chemical for cancer treatment. P16 is most frequently inactivated by copy number deletion and DNA methylation in cancers. It is well known that cancer cells with P16 deletion are more sensitive to palbociclib than those without. However, whether P16 methylation is related to palbociclib sensitivity is not known. By analyzing public pharmacogenomic datasets, we found that the IC50 of palbociclib in cancer cell lines (n = 522) was positively correlated with both the P16 expression level and P16 gene copy number. Our experimental results further showed that cancer cell lines with P16 methylation were more sensitive to palbociclib than those without. To determine whether P16 methylation directly increased the sensitivity of cancer cells to palbociclib, we induced P16 methylation in the lung cancer cell lines H661 and HCC827 and the gastric cancer cell line BGC823 via an engineered P16-specific DNA methyltransferase (P16-Dnmt) and found that the sensitivity of these cells to palbociclib was significantly increased. The survival rate of P16-Dnmt cells was significantly lower than that of vector control cells 48 hrs post treatment with palbociclib (10 μM). Notably, palbociclib treatment also selectively inhibited the proliferation of the P16-methylated subpopulation of P16-Dnmt cells, further indicating that P16 methylation can increase the sensitivity of cells to this CDK4/6 inhibitor. These results were confirmed in an animal experiment. In conclusion, inactivation of the P16 gene by DNA methylation can increase the sensitivity of cancer cells to palbociclib.

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Section: Discussioncontrasting

confidence: 67%

P16 methylation increases the sensitivity of cancer cells to the CDK4/6 inhibitor palbociclib

Zhang

et al. 2019

PLoS ONE

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“…Lung cancer is one of the most common malignant tumours in the world, accounting for 18.2% of the world's malignant tumour mortality. 12 It has also become the leading cause of malignant tumour death among Chinese urban residents. So far, although patients can obtain a range of effective treatments, including surgical resection, chemotherapy, targeted drug therapy and other methods, the prognosis of patients with NSCLC is still poor, the report pointed out that its five-year survival rate is only 11–15%.…”

Section: Discussionmentioning

confidence: 99%

Clinical value of CTLA4-associated microRNAs combined with inflammatory factors in the diagnosis of non-small cell lung cancer

et al. 2020

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Background The current study aimed to explore the value of cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-associated microRNAs combined with inflammatory factors in the differential diagnosis of non-small cell lung cancer (NSCLC). Methods A retrospective study including 245 NSCLC patients and 245 healthy controls was conducted on a testing group. A regression formula for NSCLC prediction was established based on the testing group. Two validation groups from two centres were used to assess the novel logistic regression model including 144 NSCLC patients and 144 healthy controls recruited from the Wuchang Hospital Affiliated to Wuhan University of Science and Technology, and 128 NSCLC patients and 128 healthy controls recruited from the Zhongnan Hospital of Wuhan University. Results Predictive software and dual-luciferase reporter assays showed that miR-155-5p and miR-630 could target CTLA4 expression. The miR-155-5p and miR-630 concentrations in the NSCLC patients were significantly lower, and the neutrophil to lymphocyte ratio, hypersensitive C-reactive protein (hs-CRP), interleukin 6, cytokeratin-19-fragment (CYFRA21-1), squamous cell carcinoma antigen (SCCA) concentrations and the smoking rate were significantly higher than that in healthy controls ( P < 0.05). A logistic regression model that included smoking, neutrophil to lymphocyte ratio, hs-CRP, interleukin 6, CYFRA21-1, SCCA, miR-155-5p and miR-630 was performed. This model presented a high discriminating value (AUC: 0.830, sensitivity/specificity: 74.6%/89.7%) than any single indicator. In the validation groups, this model still showed a high discriminating value (AUC = 0.838 with the internal validation group; AUC = 0.851 with the external validation group). Conclusion The current model has potential significance for the non-invasive diagnosis for NSCLC.

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“…The genes CDH1, CDKN2Ap16, RASSF1A, TERT , and WT1 were selected based on their roles as biomarkers in NSCLC and their putative gender sensitivity based on the current literature and our own research findings (reviewed in [ 64 ]). Among the selected markers, RASSF1A [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] and, to a lesser extent, CDKN2Ap16 [ 73 , 74 , 75 , 76 , 77 ] are already accepted as methylation markers. The applicability of CDH1 [ 78 , 79 , 80 , 81 , 82 , 83 ] and WT1 [ 45 , 61 , 84 , 85 ] is still under investigation but may have a broader impact on many cancer entities; their interdependence adds to this potential.…”

Section: Methodsmentioning

confidence: 99%

Promoter Methylation of Selected Genes in Non-Small-Cell Lung Cancer Patients and Cell Lines

Sarne

Huter²,

Braunmueller

et al. 2020

IJMS

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Specific gene promoter DNA methylation is becoming a powerful epigenetic biomarker in cancer diagnostics. Five genes (CDH1, CDKN2Ap16, RASSF1A, TERT, and WT1) were selected based on their frequently published potential as epigenetic markers. Diagnostic promoter methylation assays were generated based on bisulfite-converted DNA pyrosequencing. The methylation patterns of 144 non-small-cell lung cancer (NSCLC) and 7 healthy control formalin-fixed paraffin-embedded (FFPE) samples were analyzed to evaluate the applicability of the putative diagnostic markers. Statistically significant changes in methylation levels are shown for TERT and WT1. Furthermore, 12 NSCLC and two benign lung cell lines were characterized for promoter methylation. The in vitro tests involved a comparison of promoter methylation in 2D and 3D cultures, as well as therapeutic tests investigating the impact of CDH1/CDKN2Ap16/RASSF1A/TERT/WT1 promoter methylation on sensitivity to tyrosine kinase inhibitor (TKI) and DNA methyl-transferase inhibitor (DNMTI) treatments. We conclude that the selected markers have potential and putative impacts as diagnostic or even predictive marker genes, although a closer examination of the resulting protein expression and pathway regulation is needed.

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P16 Methylation Leads to Paclitaxel Resistance of Advanced Non-Small Cell Lung Cancer

Cited by 19 publications

References 37 publications

P16 methylation increases the sensitivity of cancer cells to the CDK4/6 inhibitor palbociclib

P16 methylation increases the sensitivity of cancer cells to the CDK4/6 inhibitor palbociclib

Clinical value of CTLA4-associated microRNAs combined with inflammatory factors in the diagnosis of non-small cell lung cancer

Promoter Methylation of Selected Genes in Non-Small-Cell Lung Cancer Patients and Cell Lines

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