NF1-depleted ER+ breast cancers are differentially sensitive to CDK4/6 inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1143539 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30116300.fastq.gz | Fastqsanger.gz | |||
| SRR30116301.fastq.gz | Fastqsanger.gz | |||
| SRR30116302.fastq.gz | Fastqsanger.gz | |||
| SRR30116303.fastq.gz | Fastqsanger.gz | |||
| SRR30116304.fastq.gz | Fastqsanger.gz |
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Project description:Neurofibromin/NF1-depletion (NF1low) is associated with endocrine therapy resistance in approximately 20% of ER+/HER2– early-stage breast cancer but specific treatments for NF1low tumors are not established. Proteogenomic analyses on ER+/HER2– breast cancer demonstrated that NF1low tumors exhibit elevated CDK4/6 activity. NF1-silencing in cell lines promoted ER recruitment to CCND1, thus increasing cyclin-D1 levels. Additionally, RAF is demonstrated to directly phosphorylate the CDK4 activation-loop (pT172) thus providing a direct connection between NF1 loss and an increase in CDK4 activity. Consequently, NF1low cancer cells are differentially sensitive to a fulvestrant plus CDK4/6 inhibitor (CDK4/6i) combination, with cell-death induction in vitro, and durable tumor regressions in ER+ NF1low PDX models in vivo. Furthermore, NF1low ER+/HER2– tumors treated neoadjuvantly with 4 weeks of anastrozole exhibited a minimal reduction of a multigene mRNA proliferation score vs NF1high tumors but exhibited marked sensitivity to the subsequent addition of palbociclib. In conclusion, dual ER and downstream RAF activation following NF1-loss drives endocrine therapy resistance and CDK4/6i sensitivity in NF1low ER+ breast cancer. NF1 status should therefore be prioritized for biomarker investigations in adjuvant CDK4/6i trials to determine whether the NF1low status identifies a particularly sensitive subset where CDK4/6i therapy is critical.
2025-05-27 | GSE273881 | GEO
Project description:Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omics approach to quantitatively profile kinome activation in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental Design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the effectivity of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor (LY3214996) alone and in combination to reduce PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust synergism of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor (LY3214996) in primary Nf1-/- Schwann cell cultures. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced anti-tumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusion: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
2023-06-26 | GSE213786 | GEO
Project description:Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omics approach to quantitatively profile kinome activation in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental Design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the effectivity of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor (LY3214996) alone and in combination to reduce PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust synergism of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor (LY3214996) in primary Nf1-/- Schwann cell cultures. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced anti-tumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusion: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
2023-06-26 | GSE213787 | GEO
Project description:NF1 deficiency drives metabolic reprogramming in ER+ breast cancer. This reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion, and these metabolic changes introduce novel metabolic-to-targeted inhibitor synergies.
2023-12-25 | GSE251692 | GEO
Project description:NF1 deficiency drives metabolic reprogramming in ER+ breast cancer
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Project description:The shift in the energetic demands of proliferating cells during tumorigenesis requires extensive crosstalk between the cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism in normal tissues. However, in the context of cancer, where CDK4 is upregulated or stabilized, the metabolic role of CDK4 is barely understood. Here, using both genetic and pharmacological approaches, we sought to determine the metabolic role of CDK4 in triple-negative breast cancer (TNBC) cells. Unexpectedly, the deletion of CDK4 only modestly reduced TNBC cell proliferation and did not hinder tumor formation in vivo. Furthermore, proapoptotic stimuli failed to induce appropriate cell death in TNBC cells upon CDK4 depletion or long-term CDK4/6 inhibitor treatment. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERC) formation, thereby promoting mitochondrial fission and ER-mitochondrial calcium signaling. Phosphoproteomic analysis also revealed a role for CDK4 in regulating PKA activity at MERCs to sustain ER-mitochondrial calcium signaling. Such CDK4-mediated mitochondrial calcium signaling is required for the metabolic flexibility of TNBC cells. Taken together, these results demonstrate that CDK4 inhibition leads to cell death resistance by inhibiting mitochondrial apoptosis and functions through attenuated MERCs formation and ER-mitochondrial calcium signaling in TNBC. Overall, this study provides new insights into the mechanisms of TNBC resistance to CDK4/6i therapy and paves the way to explore potential synergistic therapeutic targeting of MERCs-associated metabolic shifts.
2024-10-14 | GSE278524 | GEO
Project description:Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves the outcome of patients with advanced estrogen receptor-positive (ER+) breast cancer. However, resistance to this treatment and resultant disease progression remains a major clinical challenge. High expression of the receptor tyrosine kinase REarranged during Transfection (RET) has been associated with resistance to endocrine therapy in breast cancer, but the role of RET in CDK4/6i treatment response/resistance remains unexplored. To identify gene expression alterations associated with resistance to combined endocrine therapy and CDK4/6i, we performed global gene expression analysis and RNA sequencing of two ER+ breast cancer cell models resistant to this combined therapy.
2024-11-19 | GSE268699 | GEO
Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.
2023-07-11 | GSE236499 | GEO
Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.
2023-07-11 | GSE236497 | GEO
Project description:CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identified protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout (RBKO) breast cancer cells. Inhibition of PRMT5 blocked the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RBKO cells. Proteomics analysis uncovered fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 resulted in dissociation of FUS from RNA polymerase II (Pol II), which led to Ser2 Pol II hyperphosphorylation, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibited growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight the potential of dual ER and PRMT5 blockade as a novel therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.
2023-07-11 | GSE236498 | GEO