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An ESR1 neoepitope vaccine targeting resistance mutations induces cross-protective anti-tumor immune responses against ER+ Breast Cancer

ABSTRACT: Estrogen receptor α (ER) positivity defines ~75% of breast cancers (BCs), treated with a variety of estrogen-targeting therapies. However, ~25% of patients with localized disease and nearly all metastatic disease patients develop resistance to such therapies. One major mechanism of resistance occurs through gain-of-function mutations in the gene encoding ER (ESR1), which occurs after prolonged endocrine therapy. These gain-of-function mutations render ESR1 constitutively active and represent critical neoepitopes of ER+ BC. We here confirm that these mutations permit ligand-independent estrogen signaling, as well as stimulate alternate pathways to enhance BC oncogenicity in vivo. As these oncogenic ESR1-mutated genes (ESR1mut) may be a significant, predictable contributor to the development of acquired resistance to endocrine therapy, we explored the potential of vaccination targeting these neoepitopes. In our study, we confirmed that these peptides are presented by MHC complexes and capable of stimulating CD8+ T-cell responses. Using recombinant adenoviral vectors encoding ESR1mut, we also demonstrate the induction of ESR1-specific immunity to generate anti-tumor responses against ESR1mut-expressing BC. Finally, we improved the safety profile, ESR1-specific immunity and anti-tumor efficacy of our vaccines using c-terminal subunit ESR1mut targeting, which has the potential to prevent the outgrowth of resistant ER+ BCs and improve patient outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153033 | GEO | 2024/02/14

REPOSITORIES: GEO

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ChIP-seq: Elacestrant demonstrates strong anti-estrogenic activity in PDX models of estrogen- receptor positive endocrine-resistant and fulvestrant-resistant breast cancer

Project description:We carried out a comparative study of the orally bioavailable investigational SERD elacestrant, versus fulvestrant, in models of endocrine sensitive and resistant BC harbouring varying genetic backgrounds. Both drugs showed comparable effects on tumour growth of ER+ patient-derived xenograft models harbouring several ESR1 mutations and elacestrant showed activity after acquired resistance to fulvestrant. Treatment with either drug showed similar impact on ER-cistrome, ER- interactome and suppression of estrogen-regulated genes, confirming the anti-estrogenic activity of elacestrant.

2022-08-01 | GSE190385 | GEO

RNAseq: Elacestrant demonstrates strong anti-estrogenic activity in PDX models of estrogen- receptor positive endocrine-resistant and fulvestrant-resistant breast cancer

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Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers

Project description:<p>Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER+ BC). By genomic and metabolomics analyses of patients’ tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER+ BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER+ BC patients.Insert information here such as publication abstract</p>

2023-06-27 | MTBLS3342 | MetaboLights

Chromatin profile-based identification of a novel ER-positive breast cancer subgroup with reduced ER-responsive element accessibility

Project description:Estrogen receptor (ER) signaling–dependent cancer cell growth is one of the major features of ER-positive breast cancer (BC). Inhibition of ER function is a standard and effective treatment for ER-positive tumors; however, ~20% of patients with ER-positive BC experience early or late recurrence. In this study, we examined intertumor heterogeneity from an epigenetic perspective based on the hypothesis that the intrinsic difference in epigenetic states around ER signaling pathway underlies endocrine therapy resistance. We profiled chromatin accessibility data from 42 BC samples, including 35 ER-positive human epidermal growth factor receptor 2 (HER2)-negative and 7 triple-negative tumors, identifying a subgroup of ER-positive BCs with a distinctive chromatin accessibility pattern including reduced accessibility to ER-responsive elements (EREs). The same subgroup was also observed in The Cancer Genome Atlas BC cohort. Despite the reduced accessibility to EREs, the expression of ER and potential ER target genes were not decreased in these tumors. Our findings highlight the existence of a subset of ER-positive BCs with unchanged ER expression but reduced EREs accessibility that cannot be distinguished by conventional immunostaining for ER. Future studies should determine whether these tumors are associated with resistance to endocrine therapy.

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Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor positive breast cancer

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Phosphoproteome characterization of ESR1 mutated breast cancer cells

Project description:Three quarters of all breast cancer cases express the estrogen receptor (ER, ESR1 gene), which promotes tumor growth and constitutes a direct target for endocrine therapies. ESR1 mutations have been implicated in therapy resistance in metastatic breast cancers, in particular to aromatase inhibitors. ESR1 mutations promote constitutive ER activity and affect other signaling pathways, allowing cancer cells to proliferate by employing mechanisms within and outwith direct regulation by the ER. Although subjected to extensive genetic and transcriptomic analyses, understanding of protein alterations remains poorly investigated. Towards this, we employed an integrated mass spectrometry (MS) based proteomic approach to profile the protein and phosphoprotein differences in breast cancer cell lines expressing the frequent Y537N and Y537S ER mutations. Global proteome analysis revealed enrichment of mitotic and immune signaling pathways in ER mutant cells, while phosphoprotein analysis evidenced enriched activity of proliferation associated kinases, in particular CDKs and MTOR. Integration of protein expression and phosphorylation data revealed pathway-dependent discrepancies (motility vs proliferation) that were observed at varying degrees across mutant and wt ER cells. Additionally, protein expression and phosphorylation patterns, while under different regulation, still recapitulated the estrogen-independent phenotype of ER mutant cells.

2024-03-26 | PXD032285 | Pride

Proteomic and phosphoproteomic analysis of ESR1 mutant cells

2024-03-26 | PXD046446 | Pride

Interactomic characterization of ESR1 mutant cells

2024-03-26 | PXD032404 | Pride

Proteomic characterization of ESR1 mutant cells

2024-03-26 | PXD032369 | Pride

RNA sequencing of endocrine resistant breast cancer

Project description:*** This submission includes RNA data, with DNA files available under a different accession number*** Purpose: Endocrine therapy resistance remains the greatest challenge for treating hormone receptor positive breast cancer patients. We aim to identify molecular mechanisms underlying endocrine therapy resistance through in-depth genomic analysis of patient samples. Experimental Design: We collected tumors from 35 estrogen receptor positive breast cancer patients receiving endocrine therapy, of which 3 patients had intrinsic resistance and 19 patients developed acquired resistance. For each patient, multiple tumor specimens were collected during the course of treatment. We performed DNA whole exome sequencing and RNA sequencing on all tumor samples. DNA mutations, copy number alterations and RNA gene expression data were analyzed through supervised analyses comparing paired sensitive and resistant tumor samples to identify molecular features related to endocrine therapy resistance. Results: We identified mutations enriched in resistant tumors including ESR1 and GATA3. ESR1 D538G variant confers endocrine therapy resistance while E380Q variant confers hypersensitivity. We demonstrate that resistant tumors had distinct gene expression profiles and elevated signaling pathways including ER, HER2, GATA3, AKT, RAS and p63 signaling. Integrated analysis for individual patient highlighted the heterogeneity of endocrine therapy resistance mechanisms. Conclusions: Our results suggest that mechanisms underlying endocrine therapy resistance are highly heterogeneous with diverse changes in genomic and transcriptomic levels.

2022-09-01 | E-MTAB-9917 | biostudies-arrayexpress

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