Direct CDKN2 Modulation of CDK4 Alters Target Engagement of CDK4 Inhibitor Drugs

Green, Jennifer L.; Okerberg, Eric; Sejd, Josilyn; Palafox, Marta; Monserrat, Laia; Alemayehu, Senait; Wu, Jiangyue; Sykes, Maria; Aban, Arwin; Serra, Violeta; Nomanbhoy, Tyzoon

doi:10.1158/1535-7163.mct-18-0755

Cited by 34 publications

(34 citation statements)

References 36 publications

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“…It has been reported recently that high CDK4 target engagement by palbociclib in cells with knockout of CDKN2A gene and attenuated target engagement when CDKN2A/P16 is abundant [37]. Our bioinformatics analysis via mining public pharmacogenomic datasets indicates that the IC50 value of palbociclib is positively correlated with the transcription level of the CDKN2A gene in 522 cancer cell lines.…”

Section: Discussionmentioning

confidence: 80%

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: Discussionmentioning

confidence: 80%

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

Zhang

et al. 2019

PLoS ONE

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“…An ovarian patient with loss of CDKN2A derived significant, prolonged clinical benefit from Palbociclib with letrozole (36). High CDKN2A should be one of the exclusion criteria for CDK4/6 inhibitor therapy for high CDK4 target engagement by Palbociclib in cells without functional CDKN2A and attenuated target engagement when CDKN2A is abundant (14). GH3 cells mainly secrete growth hormone and insulin-like growth factor, and GT1-1 cells mainly secrete luteinizing hormone accompanied with a little growth hormone.…”

Section: Cdkn2a Cdkn2c Cdkn2d ---------------------------------------mentioning

confidence: 99%

“…Overexpression of cyclin E/CDK2 and loss of p21 cIP1 /p27 KIP1 appeared to be associated with poor prognosis in SOMA (13). The INK4 family shares similar domains that competes with cyclin d and relieves the activation of CDK4/6 (14), leading to cell cycle arrest in the G1/S phase (15). Loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) predicted sensitivity to the CDK4/6 inhibitor, Pd0332991, in melanoma cell lines (16).…”

Section: Introductionmentioning

confidence: 99%

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CDKN2A (p16INK4A) affects the anti‑tumor effect of CDK inhibitor in somatotroph adenomas

Chen

Fang

et al. 2020

Int J Mol Med

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The altered cell cycle is associated with aberrant growth factor signaling in somatotroph adenoma, which is the primary cause of acromegaly. The aim of the present study was to investigate the pathological role of the INK4 family and evaluate the effectiveness of CDK4 inhibitor, palbociclib, in somatotroph adenoma. RNA-Seq, RT-PcR, and immunohistochemistry were applied to measure the levels and correlations of the INK4 family with angiogenesis, cdKs, EMT, and therapeutic targets. MTS, flow cytometry, and ELISA were used to investigate the bio-activity in GH3 and GT1-1 cell lines after palbociclib treatment. compared with lactotroph adenoma, gonadotroph adenoma, and corticotroph adenoma, somatotroph samples demonstrated higher expression of CDKN2A and SSTR2 but a lower expression of EGFR, CDK4, and CDH2 (P<0.05). CDKN2A positively correlates with SSTR2, and negatively with CDK4, EGFR, and CDH2. Patients with lower CDKN2A had larger tumor size (P=0.016) and more invasive potential (P=0.023). Palbociclib inhibited cell proliferation, induced G1 phase arrest, reduced GH/IGF-1 secretion of GH3 and GT1-1 cell lines (P<0.05), and had a more prominent role in GH3 cells (P<0.05). CDKN2A inhibited the bio-activity by modulating CDK4, and high CDKN2A predicted the insensitivity to CDK4 inhibitor, palbociclib, in somatotroph adenoma patients. In summary, the present study shows CDKN2A inhibited the bio-activity by modulating CDK4, and high CDKN2A predicts the insensitivity to CDK4 inhibitor, Palbociclib, in somatotroph adenoma patients.

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“…Collectively, these results demonstrate that MILIP links c-Myc to inactivating p53. This regulation appears independent of p14 ARF as the cell lines used (A549, MCF-7, HCT116, MDA-MB-231, and U2OS) were deficient in p14 ARF expression [37][38][39][40][41][42][43] . Fig.…”

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confidence: 99%

c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis

et al. 2020

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The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.

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Direct CDKN2 Modulation of CDK4 Alters Target Engagement of CDK4 Inhibitor Drugs

Cited by 34 publications

References 36 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

CDKN2A (p16INK4A) affects the anti‑tumor effect of CDK inhibitor in somatotroph adenomas

c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis

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