Gene expression alterations associated with acquired-resistance to the CDK4/6 inhibitor palbociclib [Palbociclib resistance_RNASeq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA551944 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9622090_1.fastq.gz | Fastqsanger.gz | |||
| SRR9622090_2.fastq.gz | Fastqsanger.gz | |||
| SRR9622100_1.fastq.gz | Fastqsanger.gz | |||
| SRR9622100_2.fastq.gz | Fastqsanger.gz | |||
| SRR9622110_1.fastq.gz | Fastqsanger.gz |
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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.
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Project description:CDK4/6 kinase inhibitors have shown great promise in clinical trials in various cancer types and have recently entered clinical trial for advanced prostate cancer. Although patients are expected to respond well to this class of drugs, development of resistance in some patients is anticipated. To pre-empt this and study how prostate cancer may evade CDK4/6 inhibition, new resistance models were generated from LNCaP and LAPC4 prostate cancer cells cells by prolonged culturing in presence of 0.5uM palbociclib. A shotgun phosphoproteomics approach was utilized and integrated with RNA sequencing data to unravel the molecular underpinnings of acquired resistance to palbociclib and resultant broad CDK4/6 inhibitor resistance.
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Project description:CDK4/6 kinase inhibitors have shown great promise in clinical trials in various cancer types and have recently entered clinical trial for advanced prostate cancer. Although patients are expected to respond well to this class of drugs, development of resistance in some patients is anticipated. To pre-empt this and study how prostate cancer may evade CDK4/6 inhibition, new resistance models were generated from LNCaP and LAPC4 prostate cancer cells cells by prolonged culturing in presence of 0.5uM palbociclib. RNA sequencing data was integrated with phospho-proteomics to unravel the molecular underpinnings of acquired resistance to palbociclib and resultant broad CDK4/6 inhibitor resistance.
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Project description:BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs, and new vulnerabilities in cells after emergence of resistance.
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Project description:One potential resistance mechanism to CDK4/6 inhibitors in breast cancer could be induction of cellular senescence in normal host tissues. The aim of our study was to identify CDK4/6 inhibition-induced changes to host tissues that impact metastasis. Using mouse models, we found that pre-treatment with palbociclib can increase metastatic seeding of mouse mammary cancer cells in the lungs and that this can be mitigated by eliminating senescent host cells. We describe palbociclib-induced gene expression changes in lungs that correlate with this effect and reveal altered intra-lung immune populations. Senescent endothelial cells are identifiable within lung metastases of mice pre-treated with palbociclib. Using in vitro models, we show that palbociclib treatment increases endothelial cell senescence and affects macrophage invasion and migration. These studies describe how CDK4/6 inhibition-induced cellular senescence in host tissues affects metastasis and disease progression in breast cancer, which remain key obstacles to achieving long-term survival.
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