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Could Advances in ER Antagonism or Degradation Unlock An Alternative Future?

ER positive cancer = estrogen/oestrogen receptor positive cancer

ER Activation

ER+/HER2- tumour cells depend on different kinds of oestrogen receptor (ER) signaling activity to survive1,2

Complex and often compensatory mechanisms within ER-dependent and -independent pathways enable tumour activation and proliferation1-3

ER Pathway Activity is Prevalent

79% of breast cancer patients are ER+4


of resistant mBC tumours rely on ER⁠⁠⁠-⁠dependent activity5

And even after long term ER-degrading endocrine therapy,


of oestrogen receptors are still present6

>300 proteins interact with one or more receptor types, including the ER6

ER Pathway Activation Is Fuelling Endocrine Resistance

Both ER-dependent and -independent pathways are involved in tumour progression and treatment escape mechanisms2,7 :

  • In a series of downstream effects, aberrant signaling may lead to excess oestrogen binding in ER-dependent pathways, which can alter gene regulation and stimulate cell proliferation2,5,6
  • Endocrine therapy works to suppress overactive signaling, but in doing so it can also drive compensatory mechanisms like ER-independent signaling that can lead to endocrine resistance1,7

ER Pathway Compensatory Mechanisms

Compensatory mechanisms that confer ER stability via ER-independent pathway signaling include3:

  • lowered levels of ERs
  • ER constitutive activation
  • ligand-independent ER activation by growth factors
  • amplification of downstream ER signaling pathways

Endocrine Therapy Resistance Mechanisms Are Inevitable

These pathways are frequently upregulated and enable oestrogen-independent signaling—often fuelled by endocrine therapy1,5:

  • However, due to the potential for the ER to conduct growth signaling even after occupancy, strategies to inhibit activity between growth factors via ligand-independent activation should include ER antagonism or degradation

Can advances in ER antagonism or degradation unlock an alternative future?

HER2=human epidermal growth factor receptor 2.

Advances in ER Research

Advances in ER antagonism or degradation may offer more options

Endocrine resistance is common and may lead to disease recurrence, metastases and eventually death3,7,8

Optimising Approaches

Hospital Icon The presence of both ER-dependent and -independent mechanisms suggests that optimising antagonism or degradation of the ER pathway could help to improve outcomes5

Addressing Treatment Resistance

Microscope Icon Alternating endocrine therapies is a common approach to treatment resistance. Tumours that have developed resistance to one endocrine therapy, but continue to rely on ER-mediated signaling, respond to an alternative form of endocrine therapy1,2

However, ER-dependent tumours can adapt to develop escape pathways, which can lead to progressively shorter response times with subsequent lines of therapy. Following exposure to certain targeted therapies, cross resistance may also occur in patients5,6

Achieving ER Antagonism

DNA Icon Research suggests that the level of antagonistic effects in ER-dependent pathways may be tied to the level of degradation that occurs in the pathway3,5,6

Strong ER degradation may deliver an increase in maximal growth inhibition of the tumour cells3,5

Distinct modulation of the ER has been shown to have antagonistic effects on cell proliferation and growth9

Achieving Science

Test Tube Icon There is a renewed interest in strategies that could advance the levels of antagonism or degradation in the ER pathway. Research continues to evaluate existing and discover new mechanistic approaches that combat endocrine resistance3,5

Can advances in ER antagonism or degradation provide more options?

Explore the underlying disease mechanisms further

References: 1. Haque MM, Desai KV. Pathways to endocrine therapy resistance in breast cancer. Front Endocrinol. 2019;10:573. 2. Roy SS, Vadlamudi RK. Role of estrogen receptor signaling in breast cancer metastasis. Int J Breast Cancer. 2012. doi:10:1155/2012/654698 3. Jeffreys SA, Powter B, Balakrishnar B, et al. Endocrine resistance in breast cancer: the role of estrogen receptor stability. Cells. 2020. doi:10.3390/cells9092077 4. DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. Cancer J Clin. 2019;69(6):438-451. 5. Lin X, Xiang H, Luo G. Targeting estrogen receptor α for degradation with PROTACs: a promising approach to overcome endocrine resistance. Eur J Med Chem. 2020. doi:10:1016/j.emech.2020.112689 6. McDonnell DP, Wardell SE. The molecular mechanisms underlying the pharmacological actions of ER modulators: implications for new drug discovery in breast cancer. Curr Opin Pharmacol. 2010;10(6):620-628. 7. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233-247. 8. Lei JT, Anurag M, Haricharan S, Gou X, Ellis MJ. Endocrine therapy resistance: new insights. Breast. 2019;(48):1-11. 9. Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1-24.


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