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Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome

ABSTRACT: Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome

PROVIDER: PRJNA386948 | ENA |

REPOSITORIES: ENA

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Resistance to Palbociclib requires multiple targetable mechanisms highlighting the potential of drug holidays and drug switching to improve therapeutic outcome

Project description:Estrogen receptor positive (ER+) breast cancer is the most common type of breast cancer. Despite the great efficacy of endocrine therapies, resistance remains a problem. Therefore, there is an immediate need for new, effective therapies in ER+ BC. In this study, we have explored the role of a potent CDK4/6 inhibitor called palbociclib. In order to identify alterations in protein abundance between the responsive and resistant setting, we generated a panel of palbociclib-sensitive and resistant cell lines and did quantitative, shotgun proteomics using dimethyl labelling. Palbociclib sensitive cell lines (wt-MCF7 or MCF7-LTED) were cultured in phenol red-free RPMI supplemented with 10% FBS and 1nM estradiol or 10% dextran-coated charcoal (DCC) respectively. Thereafter, palbociclib resistant cell lines were generated using 1μΜ palbociclib concentration. Samples were harvested at baseline and at the point of resistance.

2020-03-25 | PXD005611 | Pride

Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-05-12 | GSE99003 | GEO

Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome [Illumina]

Project description:Combination of CDK4/6 inhibitors and endocrine therapy has been shown to improve clinical outcome in advanced estrogen receptor-positive breast cancer. However, not all patients will benefit and relapse is inevitable making the identification of new therapeutic strategies/biomarkers of particular importance.

2020-05-12 | GSE98987 | GEO

Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome [Affymetrix]

2020-06-23 | GSE99002 | GEO

Homo sapiens

Project description:Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome [Illumina]

| PRJNA386917 | ENA

Homo sapiens

Project description:Resistance to Palbociclib involves multiple mechanisms amenable to targeting with drug holidays or drug switching to improve therapeutic outcome [Affymetrix]

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Combined inhibition of STAT3 and DNA repair in palbociclib-resistant ER-positive breast cancer

Project description:The results from our study have identified two clinically relevant, divergent and druggable pathways (DNA repair and STAT3) that can be targeted in combination to effectively combat drug resistance. We also found that the same pathways that were deregulated in palbociclib-resistant cells were also altered in tumor samples obtained from patients who progressed while on palbociclib and endocrine therapy

2019-08-31 | GSE128056 | GEO

Investigation of the synergistic effect mechanism underlying sequential use of palbociclib and cisplatin through integral proteomic and glycoproteomic analysis

Project description:Chemoresistance largely hampers the clinical use of chemo drugs for cancer patients, combination or sequential drug treatment regimens have been designed to minimize chemotoxic and resensitize chemoresistance. In this work, the cytotoxic effect of cisplatin was found to be enhanced by palbociclib pretreatment. With the integration of proteomic and N-glycoproteomic workflow, we found that palbociclib alone mainly enhances the N-glycosylation alterations in Hela cells, while cisplatin majorly increases the DEPs (different expression proteins) including apoptosis proteins. As a result, the sequential use of two drugs induced a higher expression level of apoptosis proteins BAX and BAK. Those altered n-glycoproteins induced by palbociclib were implicated in pathways that are closely associated with cell membrane modification and drug sensitivity. Specifically, the top 4 frequently glycosylated proteins FOLR1, L1CAM, CD53, and LAMP1 were all drug resistance or drug sensitivity associated proteins located mainly in the cell membrane. It is suspected that palbociclib-induced N-glycosylation on the membrane protein allowed the Hela cell to become more vulnerable to cisplatin. Our study provided new insights into the mechanism underlying the sequential use of target drug and chemotherapy drug, meanwhile suggesting a high-efficiency approach that involves proteomic and N-glycoproteomic to facilitate drug understanding.

2022-07-09 | PXD035188 | iProX

Gene expression alterations associated with acquired-resistance to the CDK4/6 inhibitor palbociclib [Palbociclib resistance_RNASeq]

Project description:RNA-seq was performed to compare the transcriptional programmes of palbociclib-resistant A375 and CHL1 cells compared to their parental counterparts Cyclin dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor positive breast cancer and are currently in clinical development in melanoma; a tumour that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib, and demonstrated that palbociclib-mediated inhibition of PRMT5 is essential for sensitivity to CDK4/6 inhibitors. Mechanistically, by inhibiting PRMT5 activity, palbociclib alters MDM4 pre-mRNA splicing leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 increases p21 leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treatment naïve and resistant models and also delays the emergence of resistance. Our studies have uncovered a novel mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide pre-clinical evidence that co-inhibition of CDK4/6 and PRMT5 is an effective and well tolerated therapeutic strategy. Overall our data provides a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors in not only melanoma but other tumour types including breast, pancreatic and esophageal carcinoma.

2019-08-23 | GSE133567 | GEO

Characterization by RNAseq of malignant pleural mesothelioma cell lines and their response to palbociclib

Project description:Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. In this study, we evaluated the impact of CDK4/6 inhibition by palbociclib in established MPM cell lines using a variety of approaches including RNA sequencing. Palbociclib used alone sufficed to strongly and durably inhibit the proliferation of 4 of 6 cell lines. In a parallel study, the efficacy of palbociclib was confirmed in a large panel of patient-derived cell lines indicating a unique sensitivity of MPM to CDK4/6 inhibition. Importantly, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4, which was associated with the high p16 levels that accompany RB1 defects or inactivation, and also (unexpectely) CCNE1 overexpression in the presence of WT RB1. Prolonged treatment with palbociclib irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype (SASP) including various potentially immunogenic components was also irreversibly induced. Our study strongly supports the clinical evaluation of CDK4/6 inhibitory drugs for MPM treatment including in several combinatorial therapies.

2022-12-20 | GSE195568 | GEO

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