Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation

Jost, Tina; Heinzerling, Lucie; Fietkau, Rainer; Hecht, Markus; Distel, Luitpold

doi:10.3389/fonc.2021.740002

Cited by 48 publications

(21 citation statements)

References 38 publications

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“…Figure 5B demonstrates increased SA-ß-gal activity in Fulvestrant, Palbociclib and combination treated MCF7 cells when compared to untreated controls. The senescence in the combination therapy appears to be largely due to the Palbociclib ( 46 , 48 ). Figure 5C presents qRTPCR data indicating significant increases of the expression of IL-6, IL-8, and MMP3, components of the senescence-associated secretory phenotype ( 45 , 49 ), at Day 6 post-combination treatment with Fulvestrant and Palbociclib.…”

Section: Resultsmentioning

confidence: 99%

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

et al. 2023

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Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these combination therapies prolong progression-free survival compared to endocrine therapy alone, the growth-arrested state of residual tumor cells is clearly transient. Tumor cells that escape what might be considered a dormant or quiescent state and regain proliferative capacity often acquire resistance to further therapies. Our studies are based upon the observation that breast tumor cells arrested by Fulvestrant + Palbociclib enter into states of both autophagy and senescence from which a subpopulation ultimately escapes, potentially contributing to recurrent disease. Autophagy inhibition utilizing pharmacologic or genetic approaches only moderately enhanced the response to Fulvestrant + Palbociclib in ER+ MCF-7 breast tumor cells, slightly delaying proliferative recovery. In contrast, the BET inhibitor/degrader, ARV-825, prolonged the growth arrested state in both p53 wild type MCF-7 cells and p53 mutant T-47D cells and significantly delayed proliferative recovery. In addition, ARV-825 added after the Fulvestrant + Palbociclib combination promoted apoptosis and demonstrated efficacy in resistant RB deficient cell lines. These studies indicate that administration of BET inhibitors/degraders, which are currently being investigated in multiple clinical trials, may potentially improve standard of care therapy in metastatic ER+ breast cancer patients and may further prolong progression-free survival.

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Section: Resultsmentioning

confidence: 99%

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

et al. 2023

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“…Beyond this, we also identified the four candidate compounds with the most potential from a total of 2,429 compounds. Among them, palbociclib, the most pro-senescence relevant CDK4/6 inhibitor, has been documented with superior antitumor capability across HCC, melanoma, and breast cancer, through inducing a senescence phenotype ( 75 , 76 ). However, in the late stage of palbociclib treatment, enhanced HCC progression was observed in an experimental Fah -/- mouse model of HCC ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

A cellular senescence-related classifier based on a tumorigenesis- and immune infiltration-guided strategy can predict prognosis, immunotherapy response, and candidate drugs in hepatocellular carcinoma

et al. 2022

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BackgroundCellular senescence plays an irreplaceable role in tumorigenesis, progression, and tumor microenvironment (TME) remodeling. However, to date, there is limited research delineating the landscape of cellular senescence in hepatocellular carcinoma (HCC), and an improved understanding on the interaction of tumor-associated cellular senescence with HCC prognosis, TME, and response to immunotherapy is warrant.MethodsTumorigenic and immune infiltration-associated senescence genes were determined by weighted gene co-expression network analysis (WGCNA) and the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm, and subsequently, a prognostic scoring model (named TIS) was constructed using multiple survival analysis algorithms to classify the senescence-related subtypes of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were conducted to identify the distinct hallmark pathways between high- and low-risk subtypes. Additionally, we carried out correlation analyses for TIS and clinical traits, senescence-associated secretory phenotype (SASP), immune infiltration and evasion, immune checkpoint factors, drug response, and immunotherapeutic efficacy. External experimental validation was conducted to delineate the association of CPEP3 (a TIS gene) with HCC phenotypes through assays of proliferation, colony formation, and invasion.ResultsA five-gene TIS, composed of NET1, ATP6V0B, MMP1, GTDC1, and CPEB3, was constructed and validated using TCGA and ICGC datasets, respectively, and showed a highly robust and plausible signature for overall survival (OS) prediction of HCC in both training and validation cohorts. Patients in the TIS-high group were accompanied by worse OS, activation of carcinogenetic pathways, infiltration of immunosuppressive cells, exclusion of effector killing cells, overexpression of immunomodulatory genes and SASP, and unsatisfied response to immunotherapy. In response to anticancer drugs, patients in the TIS-high group exhibited enhanced susceptibility to several conventional chemotherapeutic agents (5-fluorouracil, docetaxel, doxorubicin, gemcitabine, and etoposide), as well as several inhibitors of pathways involved in cellular senescence (cell-cycle inhibitors, bromodomain and extraterminal domain family (BET) inhibitors, PI3K-AKT pathway inhibitors, and multikinase inhibitors). Additionally, four putative drugs (palbociclib, JAK3 inhibitor VI, floxuridine, and lestaurtinib) were identified as potential compounds for patients in the TIS-high group. Notably, in vitro functional validation showed that CPEB3 knockdown boosted the phenotypes of proliferation, clonogenicity, and invasion in HCC cells, whereas CPEB3 overexpression attenuated these phenotypes.ConclusionsOur study provides comprehensive clues demonstrating the role of novel TIS in predicting HCC prognosis, immunotherapeutic response, and candidate drugs. This work highlights the significance of tumorigenesis- and immune infiltration-related cellular senescence in cancer therapy.

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“…As we did not detect any significant differences in apoptosis rates between GFI1-36S and GFI1-36N cells after treatment, we assume that the higher efficacy on GFI1-36N leukemic cells was not due to increased apoptosis, but due to its effect on cell proliferation. One possible explanation may be that CDK4/6 inhibitors primarily force GFI1-36N leukemic cells to exit the cell cycle since the mechanism of initiating senescence or quiescence after CDK4/6 inhibition has been previously described by numerous groups and is currently an active field of research ( 39 , 43 – 45 ).…”

Section: Discussionmentioning

confidence: 99%

Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition

et al. 2022

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The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.

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Palbociclib Induces Senescence in Melanoma and Breast Cancer Cells and Leads to Additive Growth Arrest in Combination With Irradiation

Cited by 48 publications

References 38 publications

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

The BET inhibitor/degrader ARV-825 prolongs the growth arrest response to Fulvestrant + Palbociclib and suppresses proliferative recovery in ER-positive breast cancer

A cellular senescence-related classifier based on a tumorigenesis- and immune infiltration-guided strategy can predict prognosis, immunotherapy response, and candidate drugs in hepatocellular carcinoma

Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition

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