Transcriptional reprogramming underpinning resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE227102 | GEO | 2023/06/05
REPOSITORIES: GEO
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Project description:T47D and MCF7 cell lines were treated with long-term (continuous) palbociclib to induce 4 resistant cell-lines (T47D RB-, T47D CDK6H, MCF7 RB- and MCF7 PacqR). Each cell line (both parental and resistant) were then treated with DMSO (control), capivasertib monotherapy, fulvestrant monotherapy and capivasertib/fulvestrant combination. RNA data is available after each treatment and resistant cell lines additionally have RNA data available after continuous palbociclib treatment.
2023-08-14 | E-MTAB-13262 | biostudies-arrayexpress
Project description:We performed the Assay for Transposase-Accessible Chromatin with Sequencing (ATAC-Seq) on (i) parental MCF7 cells treated with control vehicle or abemaciclib (ii) abemaciclib- and abemaciclib/fulvestrant-resistant cells treated with control vehicle or INX-315.
2023-11-22 | GSE243147 | GEO
Project description:We performed RNA sequencing on T47D and MCF7 cells, both parental and abema- or abema/fulvestrant- resistant, treated with either control vehicle or 300 nM (MCF7) or 100 nM (T47D) INX-315 for 7 days
2023-11-22 | GSE243150 | GEO
Project description:Here we characterise the response of models of ER-positive breast cancer to treatment with the small molecule MDM2 inhibitor NVP-CGM097, a dihydroisoquinolinone derivative currently evaluated in a phase I clinical trial. We show that NVP-CGM097 reduces tumour cell viability of in vitro and in vivo models of endocrine sensitive, endocrine resistant and palbociclib (CDK4/6 inhibitor) resistant p53 wildtype (p53wt) ER-positive breast cancer. NVP-CGM097 synergises with both fulvestrant and palbociclib in models of therapy resistance. Importantly, we identify the key mechanisms of the synergistic interactions between NVP-CGM097 and endocrine therapy, which occurs through the inhibition of E2F Targets and G2M Checkpoint signalling and induction of senescence, rather than depending upon upregulation of p53 dependent apoptotic pathways. Moreover, we find these same pathways are synergistically targeted during the combination treatment of ER positive breast cancer models with NVP-CGM097 and palbociclib. This indicates the genuine potential of MDM2 inhibition as therapy in advanced ER-positive breast cancer as combination endocrine therapy and CDK4/6 inhibitor treatment becomes embedded as standard of care.
2020-04-01 | GSE140758 | GEO
Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. Cell lines were treated in biological triplicates in the absence of estrogen with or without AZD5363 for 24hours in order to identify gene changes associated with perturbation of AKT signalling
2015-06-29 | E-GEOD-69893 | biostudies-arrayexpress
Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation.
2015-06-29 | GSE69893 | 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:Purpose: Breast cancers with ESR1 mutations are resistant to antiestrogen therapy. We aimed to investigate the association of ESR1 mutations with resistance to CDK4/6 inhibitors (CDK4/6i) using real-world data analysis and experimental validation. Patients and Methods: A total of 3,958 patients with estrogen receptor-positive (ER+) metastatic breast cancer with DNA sequencing data were analyzed. Breast tumor DNA and circulating tumor (ct) DNA were sequenced using the Tempus xT tumor assay and Tempus xF liquid biopsy, respectively. Patients were stratified into either treated with CDK4/6i (breast tumors: 1,070; ctDNA: 1,885) or CDK4/6i naïve (breast tumors: 750; ctDNA: 253). Engineered MCF7 cells carrying ESR1 Y537S or D538G knock-in mutations were used to study antitumor efficacy of the CDK4/6i, palbociclib in vitro and in vivo. Results: In both xF and xT assays, ESR1 mutations were the only somatic alterations significantly more frequent in those who received CDK4/6i than those who did not. Knock-in of ESR1 Y537S or ESR1 D538G in MCF7 cells resulted in upregulation of cell cycle-related gene signatures upon treatment with CDK4/6i ± antiestrogen compared to cells with non-mutant ESR1. MCF7 xenografts harboring ESR1 Y537S and D538G mutations established in nude mice were resistant to palbociclib. Conclusions: We report herein real-world and preclinical evidence that ESR1 mutations, particularly Y537S and D538G, can drive resistance to CDK4/6 inhibitors.
2024-11-12 | GSE281302 | GEO
Project description:Purpose: Resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a major clinical problem. Recently, the CDK4/6 inhibitor palbociclib combined with letrozole was approved for treatment of ER+ advanced breast cancer, and other CDK4/6 inhibitors are being investigated in combination with different endocrine treatments. However, the role of CDK4/6 in endocrine resistance and their potential as predictive biomarkers of endocrine treatment response remains undefined. Experimental Design: We investigated the specific role of increased CDK6 expression in fulvestrant-resistant cells by gene knockdown and treatment with palbociclib, and evaluated the effect in cell proliferation, apoptosis and kinase activity. Furthermore, we evaluated CDK6 expression in metastatic samples from breast cancer patients treated or not with fulvestrant. Results: We found increased expression of CDK6 in two fulvestrant-resistant cell models vs. sensitive cells. Reduction of CDK6 expression impaired fulvestrant-resistant cell growth and induced apoptosis by reducing p70 ribosomal S6 kinase 2 activity. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma phosphorylation. High CDK6 levels in metastatic samples from breast cancer patients treated with fulvestrant (N=45) correlated significantly with shorter progression-free survival (PFS) (p=0.0006), while no association was observed in patients receiving other endocrine treatments (N=41, p=0.874). Conclusions: Our results indicate that upregulation of CDK6 may be an important mechanism in overcoming fulvestrant-mediated growth inhibition in breast cancer cells. Patients with advanced ER+ breast cancer exhibiting high CDK6 expression in the metastatic lesions show shorter PFS upon fulvestrant treatment and thus may benefit from the addition of CDK4/6 inhibitors in their therapeutic regimens.
2017-02-08 | GSE74391 | GEO
Project description:CDK4/6 inhibitors are highly effective against ER+/HER2- breast cancer (BC); however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6 inhibitors may lead to the identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Parental BC cells and their endocrine-resistant derivatives (EndoR) were used in this study. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. We found that parental and EndoR BC lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high Interferon (IFN) signaling and reduced sensitivity to CDK4/6 inhibitors, thus an ‘IFN-Related Palbociclib-Resistance Signature’ (IRPS) was derived. In two neoadjuvant trials of a CDK4/6 inhibitor plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6 inhibition. PalboR derivatives displayed a dramatic activation of IFN/STAT1-signaling compared to their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Our study demonstrates that aberrant IFN-signaling is associated with intrinsic resistance to CDK4/6 inhibitors. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN-pathway, which warrants additional studies to clarify its involvement in resistance to CDK4/6 inhibitors.
2021-12-04 | GSE150997 | GEO