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Target: ESR1


Research on the Target ESR1

1. Target Summary:

ESR1, or estrogen receptor 1, encodes the estrogen receptor alpha (ERα), a key transcription factor involved in the regulation of genes that control various physiological processes, including reproductive functions and breast cancer development. Mutations in ESR1 are commonly associated with endocrine therapy resistance in estrogen receptor-positive (ER+) breast cancer, particularly in metastatic cases. These mutations can lead to ligand-independent receptor activation, promoting tumor growth and progression.

2. Mechanism:

ESR1 mutations primarily occur in the ligand-binding domain (LBD) of the estrogen receptor, leading to constitutive activation of the receptor even in the absence of estrogen. This results in increased transcriptional activity of estrogen-responsive genes, which contributes to tumor growth and survival.
  • Ligand-Independent Activation: Mutations such as Y537S and D538G allow the receptor to activate transcription without estrogen binding, leading to continuous cell proliferation and survival signals (Jeselsohn et al., 2015; PMID: 26122181).
  • Altered Transcriptional Profile: ESR1 mutations can change the receptor's interaction with coactivators and corepressors, resulting in a unique transcriptional profile that favors tumor progression (Dustin et al., 2019; PMID: 31318440).
  • Resistance Mechanisms: The presence of ESR1 mutations is associated with acquired resistance to aromatase inhibitors and selective estrogen receptor modulators (SERMs), as these therapies typically rely on the receptor's dependence on estrogen for activation (Reinert et al., 2018; PMID: 29666928).

3. Approved Drugs:

  • Fulvestrant: A selective estrogen receptor downregulator (SERD) used to treat ER+ breast cancer, particularly in patients with ESR1 mutations.
  • CDK4/6 Inhibitors: Drugs like palbociclib are often used in combination with endocrine therapies to improve outcomes in patients with ESR1 mutations (Fribbens et al., 2016; PMID: 27269946).

4. Hypotheses:

  • Resistance Hypothesis: ESR1 mutations lead to resistance against standard endocrine therapies, necessitating the development of targeted therapies that can effectively inhibit mutant receptors (Jeselsohn et al., 2015; PMID: 26122181).
  • Prognostic Biomarker Hypothesis: ESR1 mutations may serve as prognostic and predictive biomarkers, indicating a more aggressive disease and guiding treatment decisions (Carausu et al., 2019; PMID: 31188645).

5. Validation:

  • Clinical Studies: Studies have shown that patients with ESR1 mutations have poorer outcomes with traditional therapies compared to those without mutations. For instance, in the PALOMA3 trial, patients with ESR1 mutations had different responses to fulvestrant plus palbociclib compared to those with wild-type ESR1 (Fribbens et al., 2016; PMID: 27269946).
  • Liquid Biopsy: The use of liquid biopsies to detect ESR1 mutations has been validated as a method to predict treatment outcomes and guide therapy (Dustin et al., 2019; PMID: 31318440).

6. Clinical Trials:

  • SERENA-6: A phase III trial evaluating the efficacy of switching to camizestrant upon detection of ESR1 mutations in circulating tumor DNA (Turner et al., 2023; PMID: 37070653).
  • PADA-1: A trial assessing the impact of switching to fulvestrant and palbociclib in patients with rising ESR1 mutations during aromatase inhibitor therapy (Bidard et al., 2022; PMID: 36183733).

7. Involved Pathways:

  • Estrogen Signaling Pathway: ESR1 mutations disrupt normal estrogen signaling, leading to aberrant activation of downstream targets involved in cell proliferation and survival.
  • MAPK Pathway: Alterations in signaling pathways, including the MAPK pathway, are often observed in endocrine-resistant tumors (Razavi et al., 2018; PMID: 30205045).

8. Associated Genes:

  • ESR1: The primary gene of interest, mutations in which lead to altered receptor function.
  • PIK3CA: Mutations in this gene are often co-occurring with ESR1 mutations and are associated with resistance mechanisms (Hortobagyi et al., 2018; PMID: 29718092).

9. Target Expression:

ESR1 is predominantly expressed in hormone-responsive tissues, including breast tissue. Its expression is crucial for the development and progression of ER+ breast cancer.

10. Additional Context:

The emergence of ESR1 mutations is often a consequence of selective pressure from endocrine therapies, highlighting the need for ongoing monitoring and personalized treatment strategies in breast cancer management (Saatci et al., 2021; PMID: 34623477).

11. References:

  1. Jeselsohn R, Buchwalter G, De Angelis C. ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. Nature Reviews Clinical Oncology. 2015; PMID: 26122181.
  2. Dustin D, Gu G, Fuqua SAW. ESR1 mutations in breast cancer. Cancer. 2019; PMID: 31318440.
  3. Fribbens C, O'Leary B, Kilburn L. Plasma ESR1 Mutations and the Treatment of Estrogen Receptor-Positive Advanced Breast Cancer. Journal of Clinical Oncology. 2016; PMID: 27269946.
  4. Turner N, Huang-Bartlett C, Kalinsky K. Design of SERENA-6, a phase III switching trial of camizestrant in ESR1-mutant breast cancer during first-line treatment. Future Oncology. 2023; PMID: 37070653.
  5. Bidard FC, Hardy-Bessard AC, Dalenc F. Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. The Lancet Oncology. 2022; PMID: 36183733.
  6. Razavi P, Chang MT, Xu G. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell. 2018; PMID: 30205045.
  7. Saatci O, Huynh-Dam KT, Sahin O. Endocrine resistance in breast cancer: from molecular mechanisms to therapeutic strategies. Journal of Molecular Medicine. 2021; PMID: 34623477.
  8. Carausu M, Bidard FC, Callens C. ESR1 mutations: a new biomarker in breast cancer. Expert Review of Molecular Diagnostics. 2019; PMID: 31188645.
  9. Reinert T, Goncalves R, Bines J. Implications of ESR1 Mutations in Hormone Receptor-Positive Breast Cancer. Current Treatment Options in Oncology. 2018; PMID: 29666928.