CDK4 phosphorylation status and corresponding gene expression profile predict sensitivity to Palbociclib

Raspé, Eric; Coulonval, Katia; Pita, Jaime Miguel Gomes; Paternot, Sabine; Rothé, Françoise; Twijffels, L.; Laere, S. Van; Ignatiadis, M.; Sotiriou, Christos; Roger, Pierre P.

doi:10.1093/annonc/mdx138.011

Cited by 19 publications

(42 citation statements)

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“…In another study, IC 50 values calculated by BrdU incorporation assay were 15 nmol/L for both cells. 33 Consistently, both palbociclib and ActA showed cytostatic effects in T47D cells in a BrdU incorporation assay ( Figure 1B,C); these effects were additive in nature. A similar tendency was obtained in an EdU incorporation assay using flow cytometry ( Figure S1).…”

Section: Palbociclib and Activin Cooperatively Inhibit Cell Cycle Psupporting

confidence: 62%

Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer

et al. 2018

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Cyclin‐dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D‐CDK4/6‐retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin‐SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6‐mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2‐dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP‐seq data of T47D cells with those of Hs578T (triple‐negative breast cancer cells) indicated that palbociclib augmented different SMAD2‐mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin‐SMAD2 signaling pathway, whereas it possibly strengthens the tumor‐promoting aspect in aggressive breast cancer.

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Section: Palbociclib and Activin Cooperatively Inhibit Cell Cycle Psupporting

confidence: 62%

Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer

et al. 2018

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“…E, Representative images of immunohistochemical staining of Ki-67, Rb, P-Rb (S795), CDK4, CDK6, E-cadherin, N-cadherin and snail/slug in tissue from mice with different kinds of orthotopic tumor association with PD 0332991. 41,42 While Roger PP's group supposed the phosphorylated CDK4 could potentially predict sensitivity to CDK4/6 blockade, 43 this was not confirmed later in clinical results. 44…”

Section: Discussionmentioning

confidence: 99%

HOTAIR, a long noncoding RNA, is a marker of abnormal cell cycle regulation in lung cancer

Liu

Zhang

et al. 2018

Cancer Science

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Dysregulation of the cell cycle is a key indicator of tumors, including lung cancer. Recently, the study of cell cycle inhibitors has made great progress in relation to lung cancer. However, the question of what kinds of patients can use cell cycle inhibitors has plagued us. Therefore, seeking an accurate and convenient marker for the abnormal cell cycle in lung cancer is very important. In the present research, we showed that lncRNA HOTAIR is an optimal indicator of cell cycle dysregulation in lung cancer. In the present study, we investigated HOTAIR‐specific expression in lung primary tumor samples by analyzing the TCGA public database and 67 pairs of patients’ tissues collected from our department. Through the TCGA public database KEGG analysis, HOTAIR correlates with the cell cycle pathway. We identified that HOTAIR and its 2 segments, HOTAIR3′ and HOTAIR5′, promote the cell cycle passing through the restriction point during G1‐S phase by regulating the Rb‐E2F pathway and influence non–small‐cell lung cancer cell proliferation, migration and invasion through epithelial‐mesenchymal transition (EMT) and the β‐catenin pathway in vitro and vivo. Finally, we showed that the high expression of HOTAIR was associated with resistance to gefitinib through the dysregulated cell cycle. In conclusion, HOTAIR could be an ideal indicator of cell cycle dysregulation and guide the use of cell cycle inhibitors.

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“…In MCF7 lysates, 0.5 mmol/L palbociclib treatment reduced the amount of probe-labeled CDK4 to 18% of corresponding control samples (DMSO-treated MCF7 lysate). The MDA-MB-231 cell line represents a triple-negative (ER À /PR À / HER2 À ) tumor type that would currently be excluded from CDK4/6 inhibitor treatment, although the cells are in fact biologically sensitive to palbociclib as measured by cell counting (17) or BrdUrd labeling (19). MDA-MB-231 cells are RB-proficient and harbor genomic deletion of CDKN2A (14,20).…”

Section: Cdkn2a-cdk4 Interaction Determines Cdk4 Target Engagement Bymentioning

confidence: 99%

“…Notably, despite effective target engagement, DU-145 cells are biologically insensitive to palbociclib due to RB1 deficiency (21,24). Resistance mechanisms downstream of CDK4, such as by increased Cyclin E1 activity and CDK2 activation (19,21,(25)(26)(27) have been reported. For example, HCC-1806 cells, which are RB1 wild type and CDKN2A À , are reported to be resistant to palbociclib due to Cyclin E-mediated bypass of CDK4 (19,21).…”

Section: Cdkn2a-cdk4 Interaction Determines Cdk4 Target Engagement Bymentioning

confidence: 99%

“…Resistance mechanisms downstream of CDK4, such as by increased Cyclin E1 activity and CDK2 activation (19,21,(25)(26)(27) have been reported. For example, HCC-1806 cells, which are RB1 wild type and CDKN2A À , are reported to be resistant to palbociclib due to Cyclin E-mediated bypass of CDK4 (19,21). Consistent with this alternate mechanism of resistance, target engagement was observed in HCC-1806 cells.…”

Section: Cdkn2a-cdk4 Interaction Determines Cdk4 Target Engagement Bymentioning

confidence: 99%

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

Green

Okerberg

Sejd

et al. 2019

Molecular Cancer Therapeutics

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The interaction of a drug with its target is critical to achieve drug efficacy. In cases where cellular environment influences target engagement, differences between individuals and cell types present a challenge for a priori prediction of drug efficacy. As such, characterization of environments conducive to achieving the desired pharmacologic outcome is warranted. We recently reported that the clinical CDK4/6 inhibitor palbociclib displays cell type-specific target engagement: Palbociclib engaged CDK4 in cells biologically sensitive to the drug, but not in biologically insensitive cells. Here, we report a molecular explanation for this phenomenon. Palbociclib target engagement is determined by the interaction of CDK4 with CDKN2A, a physiologically relevant protein inhibitor of CDK4. Because both the drug and CDKN2A prevent CDK4 kinase activity, discrimination between these modes of inhi-bition is not possible by traditional kinase assays. Here, we describe a chemo-proteomics approach that demonstrates high CDK4 target engagement by palbociclib in cells without functional CDKN2A and attenuated target engagement when CDKN2A (or related CDKN2/INK4 family proteins) is abundant. Analysis of biological sensitivity in engineered isogenic cells with low or absent CDKN2A and of a panel of previously characterized cell lines indicates that high levels of CDKN2A predict insensitivity to palbociclib, whereas low levels do not correlate with sensitivity. Therefore, high CDKN2A may provide a useful biomarker to exclude patients from CDK4/6 inhibitor therapy. This work exemplifies modulation of kinase target engagement by endogenous proteinaceous regulators and highlights the importance of cellular context in predicting inhibitor efficacy.

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CDK4 phosphorylation status and corresponding gene expression profile predict sensitivity to Palbociclib

Cited by 19 publications

References 0 publications

Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer

Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer

HOTAIR, a long noncoding RNA, is a marker of abnormal cell cycle regulation in lung cancer

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

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