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O-GlcNAcylation promotes Palbociclib resistance in breast cancer by regulating MITF nuclear translocation

ABSTRACT: Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies MITF with O-GlcNAcylation at Serine 49 (Ser49) within its nuclear localization signal (NLS), thereby promoting MITF binding to importin α/ β and facilitating its nuclear transportation, which is crucial in regulating senescence.

INSTRUMENT(S): LCQ Classic

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: YI ZHANG

LAB HEAD: Wenge Zhu

PROVIDER: PXD042838 | Pride | 2024-05-30

REPOSITORIES: Pride

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O-GlcNAcylation promotes Palbociclib resistance in breast cancer by regulating MITF nuclear translocation

Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Then we found that MITF is interacting with OGT in Palbociclib-resistance cells, and we also identified that Ser49 is the main O-GlcNAc site of MITF. O-GlcNAc of MITF is critical to mediated Palbociclib-resistance in cells.

2024-05-30 | PXD042763 | Pride

O-GlcNAcylation promotes Palbociclib resistance in breast cancer by regulating MITF nuclear translocation [ChIP-seq]

Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies MITF with O-GlcNAcylation at Serine 49 (Ser49) within its nuclear localization signal (NLS), thereby promoting MITF binding to importin α/ β and facilitating its nuclear transportation, which is crucial in regulating senescence. Significantly, clinical studies also confirm that MITF was elevated in palbociclib-resistance patients. Collectively, these results reveal a previously unrecognized mechanism by which MITF-mediated palbociclib resistance, and provide valuable insights for the development of innovative therapeutic strategies in future clinical contexts.

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O-GlcNAcylation promotes Palbociclib resistance in breast cancer by regulating MITF nuclear translocation [RNA-seq]

Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies MITF with O-GlcNAcylation at Serine 49 (Ser49) within its nuclear localization signal (NLS), thereby promoting MITF binding to importin α/ β and facilitating its nuclear transportation, which is crucial in regulating senescence. Significantly, clinical studies also confirm that MITF was elevated in palbociclib-resistance patients. Collectively, these results reveal a previously unrecognized mechanism by which MITF-mediated palbociclib resistance, and provide valuable insights for the development of innovative therapeutic strategies in future clinical contexts.

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Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive organoids derived from patient derived xenografts from patients who progressed on palbociclib

Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.

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Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive breast cancer cell lines: MCF-7 and T47D

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

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Genome wide transcriptome analysis of palbociclib or GSK3326595 treated A375 cells [Palbociclib_GSK_RNASeq]

Project description:RNA-seq was performed to compare the transcriptional programmes of A375 cells treated with Palbociclib or GSK3326595 compared to untreated cells 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 | GSE133568 | GEO