Dataset Information

Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer.

ABSTRACT: Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen-binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent explorations of drug sensitivity validated RET kinase as a common therapeutic vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural diversity. Organoids and xenografts from a pan-ET-resistant patient-derived xenograft model that harbors the ESR1-e6>YAP1 TAF were concordantly inhibited by the selective RET inhibitor pralsetinib to a similar extent as the CDK4/6 inhibitor palbociclib. Together, these findings provide preclinical rationale for clinical evaluation of RET inhibition for the treatment of ESR1-TAF-driven ET-resistant breast cancer.

Significance

Kinome analysis of ESR1 translocated and mutated breast tumors using drug bead-based mass spectrometry followed by drug-sensitivity studies nominates RET as a therapeutic target. See related commentary by Wu and Subbiah, p. 3159.

SUBMITTER: Gou X

PROVIDER: S-EPMC10543968 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer.

Gou Xuxu X Kim Beom-Jun BJ Anurag Meenakshi M Lei Jonathan T JT Young Meggie N MN Holt Matthew V MV Fandino Diana D Vollert Craig T CT Singh Purba P Alzubi Mohammad A MA Malovannaya Anna A Dobrolecki Lacey E LE Lewis Michael T MT Li Shunqiang S Foulds Charles E CE Ellis Matthew J MJ

Cancer research 20231001 19

Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen-binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diver ...[more]

PMID: 37071495

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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

Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer.

Significance

Publications

Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer.

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