Dataset Information

Elucidation of Novel Therapeutic Targets for Breast Cancer with ESR1-CCDC170 Fusion.

ABSTRACT: Among the various types of breast cancer, the luminal B subtype is the most common in young women, and ESR1-CCDC170 (E:C) fusion is the most frequent oncogenic fusion driver of the luminal B subtype. Nevertheless, treatments targeting E:C fusion has not been well established yet. Hence, the aim of this study is to investigate potential therapies targeting E:C fusion based on systematic bioinformatical analysis of the Cancer Genome Atlas (TCGA) data. One thousand related genes were extracted using transcriptome analysis, and major signaling pathways associated with breast cancer were identified with over-representation analysis. Then, we conducted drug-target network analysis based on the OncoKB and CIViC databases, and finally selected potentially applicable drug candidates. Six major cancer-related signaling pathways (p53, ATR/ATM, FOXM1, hedgehog, cell cycle, and Aurora B) were significantly altered in E:C fusion-positive cases of breast cancer. Further investigation revealed that nine genes (AURKB, HDAC2, PLK1, CENPA, CHEK1, CHEK2, RB1, CCNA2, and MDM2) in coordination with E:C fusion were found to be common denominators in three or more of these pathways, thereby making them promising gene biomarkers for target therapy. Among the 21 putative actionable drugs inferred by drug-target network analysis, palbociclib, alpelisib, ribociclib, dexamethasone, checkpoint kinase inhibitor AXD 7762, irinotecan, milademetan tosylate, R05045337, cisplatin, prexasertib, and olaparib were considered promising drug candidates targeting genes involved in at least two E:C fusion-related pathways.

SUBMITTER: Jeong JH

PROVIDER: S-EPMC7913953 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Elucidation of Novel Therapeutic Targets for Breast Cancer with <i>ESR1-CCDC170</i> Fusion.

Jeong Jae Heon JH Yun Jae Won JW Kim Ha Young HY Heo Chan Yeong CY Lee Sejoon S

Journal of clinical medicine 20210204 4

Among the various types of breast cancer, the luminal B subtype is the most common in young women, and <i>ESR1-CCDC170</i> (E:C) fusion is the most frequent oncogenic fusion driver of the luminal B subtype. Nevertheless, treatments targeting E:C fusion has not been well established yet. Hence, the aim of this study is to investigate potential therapies targeting E:C fusion based on systematic bioinformatical analysis of the Cancer Genome Atlas (TCGA) data. One thousand related genes were extract ...[more]

PMID: 33557149

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Project description:BACKGROUND:Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. METHODS:The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. RESULTS:Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib. CONCLUSION:ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.

Project description:BackgroundEstrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer.Patients and methodsTo identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots.ResultsWe identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations.ConclusionsCollectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

Dataset Information

Elucidation of Novel Therapeutic Targets for Breast Cancer with ESR1-CCDC170 Fusion.

Publications

Elucidation of Novel Therapeutic Targets for Breast Cancer with <i>ESR1-CCDC170</i> Fusion.

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