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Targeting ferroptosis resistance re-sensitizes metastatic HR+ HER2- breast cancer to palbociclib-hormone therapy

ABSTRACT: Targeting ferroptosis resistance re-sensitizes metastatic HR+ HER2- breast cancer to palbociclib-hormone therapy

PROVIDER: PRJNA1124870 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29433307_1.fastq.gz	Fastqsanger.gz
	SRR29433307_2.fastq.gz	Fastqsanger.gz
	SRR29433308_1.fastq.gz	Fastqsanger.gz
	SRR29433308_2.fastq.gz	Fastqsanger.gz
	SRR29433309_1.fastq.gz	Fastqsanger.gz

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Targeting ferroptosis resistance re-sensitizes metastatic HR+ HER2- breast cancer to palbociclib-hormone therapy

Project description:HR+HER2- breast cancers resistant to palbociclib-hormone therapy displayed increased lipid uptake and expression of stress response proteins (GPX4, PSMA7), by adding ferroptosis inducers to palbocilib-fulvestrant combination therapy, tumor response was enhanced in three different pre-clinical models: resistant cells, xenografts and PDX.

2025-01-06 | GSE270021 | GEO

TRIB3 inhibition by palbociclib sensitizes prostate cancer to ferroptosis via SOX2-mediated SLC7A11 downregulation

Project description:Palbociclib is a CDK4/6 inhibitor approved for the treatment of breast cancer by suppressing cell proliferation. However, monotherapy with palbociclib was discouraging in prostate cancer, calling for a mechanism-based effective therapy. In this study, we reported in prostate cancer that palbociclib is a potent sensitizer of ferroptosis, which is worked out by downregulating the expression of TRIB3, a gene highly expressed in prostate cancer. Specifically, TRIB3 knockdown augmented the response of prostate cancer cells to ferroptosis inducers, whereas, TRIB3 overexpression rescued prostate cancer cells from palbociclib-induced ferroptosis. Mechanistically, TRIB3 inhibition by palbociclib resulted in downregulation of SOX2, which subsequently led to compromised expression of SLC7A11, a cystine/glutamate antiporter that counteracts ferroptosis. Functionally, a combined treatment of palbociclib with ferroptosis inducer significantly suppressed prostate cancer growth in a xenograft tumor model. Together, these results uncover an essential role of TRIB3/SOX2/SLC7A11 axis in palbociclib-induced ferroptosis, suggesting palbociclib a promising targeted therapy in combine with ferroptosis induction for the treatment of prostate cancer.

2024-10-31 | GSE273622 | GEO

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.

2023-07-10 | GSE229146 | GEO

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

2023-07-10 | GSE222367 | GEO

TRIB3 inhibition by palbociclib sensitizes prostate cancer to ferroptosis via SOX2-mediated SLC7A11 downregulation

Project description:TRIB3 inhibition by palbociclib sensitizes prostate cancer to ferroptosis via SOX2-mediated SLC7A11 downregulation

| PRJNA1142522 | ENA

HR+/HER2- Breast Cancer Cell and Normal Breast Epithelial Cell Derived Exosome RNA Expression

Project description:AS a key medium for intercellular communication, exosome plays an important role in the occurrence and development of various forms of cancers, including breast cancer. However, the RNA from breast cancer-derived exosome remains to be explored. The HR+/HER2− breast cancer is the most common subgroup of breast cancer, we collected and primary cultured breast cancer and normal breast epithelial cells from three HR+/HER2− breast cancer patients, isolated the supernatant and extracted RNA from exosomes, and then performed microarray assays.

2023-10-01 | GSE207304 | GEO

Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade

Project description:Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, homologous recombination (HR) status-dependent glycosylation has never been explored therapeutically. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe a unique enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their resistance to anti-PD-L1 by enhancing its binding with PD-1 on CD8_ T cells. In orthotopic syngeneic EOC mouse models, inhibiting branched N-glycans, using 2-Deoxy-D-glucose, sensitizes HR-proficient, but not HR-deficient EOCs, to anti-PD-L1. These findings indicate branched N-glycans as promising therapeutic targets whose inhibition sensitizes HR-proficient EOCs to ICB by overcoming immune evasion

2024-03-11 | GSE244012 | GEO

Characterizing of Breast Cancer translational PEARL clinical trial

Project description:Introduction In HR+/HER2- metastatic breast cancer (MBC) is imperative to identify patients who respond poorly to CDK4/6i and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting but further validation is needed. Methods We performed mRNA gene expression profiling and correlation with progression-free-survival (PFS) on 455 tumor samples included in the phase III PEARL study, that assigned HR+/HER2- MBC patients to receive palbociclib+ET vs capecitabine. ER+/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. Results Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4months (m) with palbociclib+ET and 9.3m with capecitabine; HR:4.16, adjusted p-value<0.0001. Tumors with high CCNE1 expression (above median) had also worse median PFS with palbociclib+ET (6.2m) than with capecitabine (9.3m); HR:1.55, adjusted p-value=0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile) we found higher levels of Polo Like Kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models we show that PLK1 inhibition reverses resistance to palbociclib+ET. Conclusion We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.

2023-01-26 | GSE223700 | GEO

Targeting Glycomes Sensitizes Ovarian Tumors to Immune Checkpoint Blockade II

2024-09-29 | GSE244367 | GEO

MUC1-C DEPENDENCY IN DRUG RESISTANT HR+/HER2- BREAST CANCER IDENTIFIES A NEW TARGET FOR TREATMENT WITH AN ANTIBODY-DRUG CONJUGATE

Project description:MUC1-C is a common effector of treatment resistant HR+/HER2- BC cells and is a potential target for their treatment

2025-04-17 | GSE272989 | GEO