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<p>Next-generation selective estrogen receptor-α (ERα) antagonist/degraders (SERDs) are being developed for ER-positive breast cancer (ER<sup>+</sup> BC), with intentions of improving outcomes for patients. In recent clinical trials of metastatic ER<sup>+</sup> BC, next-generation SERDs demonstrated clinical activity, and elacestrant received an approval for advanced <i>ESR1</i>-mutant disease. However, responses to these drugs were highly heterogeneous: across trials and independent of <i>ESR1</i> status, 30–50% of patients progressed by their first follow-up scan while other patients sustained benefit for 2 years or more. Here, we interrogate the basis for heterogeneous responses by comparing biopsies from non-responding patients (NR; progression-free survival &lt;2 months) and responding patients (Resp; PFS ≥ 2 months) who received the next-generation SERD giredestrant. While Resp tumors maintain high dependency on ERα signaling, NR tumors exhibit loss of luminal lineage identity and by extension, ERα dependence. NR tumors instead up-regulate multiple ERα-independent proliferative pathways, such as EGFR/MAPK and Hippo/TEAD, which may represent targetable dependencies in NR disease. Modeling resistance and lineage plasticity in vitro, we find that giredestrant-resistant ER<sup>+</sup> BC cell lines exhibit profound shifts in chromatin accessibility, with the transcription factors, FOXA1 and FOXM1, implicated in gene expression of NR-upregulated proliferative pathways.</p>

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Loss of luminal lineage drives resistance to next-generation ERα antagonists in pretreated ER+ HER2− locally-advanced or metastatic breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月1日

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  • Jackson Liang,
  • Christy Ong,
  • Kareem Heslop,
  • Jane Guan,
  • Vasumathi Kameswaran,
  • Bence Daniel,
  • Minyi Shi,
  • Yuxin Liang,
  • Jennifer M. Giltnane,
  • Junko Aimi,
  • Ching-Wei Chang,
  • Mary R. Gates,
  • Jennifer Eng-Wong,
  • Pablo Perez-Moreno,
  • Komal L. Jhaveri,
  • Nicholas C. Turner,
  • Elgene Lim,
  • Ciara Metcalfe,
  • Heather M. Moore

摘要

Next-generation selective estrogen receptor-α (ERα) antagonist/degraders (SERDs) are being developed for ER-positive breast cancer (ER+ BC), with intentions of improving outcomes for patients. In recent clinical trials of metastatic ER+ BC, next-generation SERDs demonstrated clinical activity, and elacestrant received an approval for advanced ESR1-mutant disease. However, responses to these drugs were highly heterogeneous: across trials and independent of ESR1 status, 30–50% of patients progressed by their first follow-up scan while other patients sustained benefit for 2 years or more. Here, we interrogate the basis for heterogeneous responses by comparing biopsies from non-responding patients (NR; progression-free survival <2 months) and responding patients (Resp; PFS ≥ 2 months) who received the next-generation SERD giredestrant. While Resp tumors maintain high dependency on ERα signaling, NR tumors exhibit loss of luminal lineage identity and by extension, ERα dependence. NR tumors instead up-regulate multiple ERα-independent proliferative pathways, such as EGFR/MAPK and Hippo/TEAD, which may represent targetable dependencies in NR disease. Modeling resistance and lineage plasticity in vitro, we find that giredestrant-resistant ER+ BC cell lines exhibit profound shifts in chromatin accessibility, with the transcription factors, FOXA1 and FOXM1, implicated in gene expression of NR-upregulated proliferative pathways.