Michael McCuskey

Background: Breast cancer is the most common form of cancer in the United States of America with 250,000 new cases annually.¹ In estrogen receptor (ER) positive breast cancer, estrogen stimulation is needed for the proliferation of tumor tissue. The estrogen receptor is an intranuclear receptor which promotes the transcription of various growth-related genes.^1,2 Estrogen suppression is a key mechanism of cancer control in metastatic cases where surgical intervention would be ineffective. Currently, aromatase inhibitors which block peripheral conversion of other steroids into estrogen are the first line therapy in menopausal women, but in premenopausal women, ovarian estrogen production means inhibition of peripheral conversion is inadequate.³ Selective estrogen receptor degraders (SERDs), such as Fulvestrant, are the current first line therapy for metastatic ER+ breast cancer in premenopausal women but tumors inevitably develop resistance.^2,3 A new method for down regulating estrogen receptor activity that is less likely to have resistance develop is key to continued treatment of ER+ breast cancer.^1,3

Objective: In this review the mechanism by which existing and novel SERDs work and allow resistance to develop along with how novel PROTACs can prevent these resistance mechanisms from progressing is investigated.

Search Methods: A search through the PubMed research database was performed looking for primary research articles published between 2019 and 2024 with the following search terms: “Breast Cancer”, “SERD”, “PROTAC”, “Resistance”, “Estrogen Receptor”

Results:  Studies indicate that the SERD Fulvestrant does not cause degradation by causing direct ubiquitin tagging of the estrogen receptor, the traditional proposed mechanism, but instead causes an arrest in nuclear mobility. By arresting the nuclear mobility of the estrogen receptor, the receptor cannot move around and promote various genes and is eventually degraded after staying in one place for too long. This mechanism explains why Fulvestrant is effective at doses much smaller than those required to cause the amount of receptor degradation needed to affect cell proliferation.⁷ Similarly, Elacestrant, a novel SERD designed to be effective in Fulvestrant resistant tumors also shows a similar dose effect, indicating a similar mechanism is occurring.⁶ The exact nature of the mechanism which causes nuclear arrest is unclear but many of the common mutations to the ER found in refractory cancers still allow the drug to bind, but not for nuclear arrest to occur.⁷ Proteolysis Targeting Chimeras (PROTACs) are a class of drugs which allow for a ubiquitin recruiting moiety to be linked to a protein targeting ligand, thus allowing direct recruitment of the Ubiquitin system if a protein can be bound.^4,5,8  ARV 471, a novel PROTAC, shows strong degradation of the estrogen receptor in vivo and was demonstrated to decrease the growth of tumors in euthymic mice with ER+ human breast cancer tumors.⁴ ZD 12 is another PROTAC showing similar promising results.⁵ Additionally, PROTACS can use DNA Oligonucleotides as the targeting ligand, meaning high specificity and low resistance potential is possible, if limitations in intracellular transport and degradation can be overcome.⁸

Conclusions: PROTACs are a novel class of drugs that can suppress estrogen receptor activity, even in tumors resistant to traditional endocrine therapy

 Works Cited

1. 1.Hanker AB, Sudhan DR, Arteaga CL. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell. 2020;37(4):496-513. doi:10.1016/j.ccell.2020.03.009
2. 2.Rasha F, Sharma M, Pruitt K. Mechanisms of endocrine therapy resistance in breast cancer. Mol Cell Endocrinol. 2021;532:111322. doi:10.1016/j.mce.2021.111322
3. 3.Dustin D, Gu G, Fuqua SAW. ESR1 mutations in breast cancer. Cancer. 2019;125(21):3714-3728. doi:10.1002/cncr.32345
4. 4.Chen Z, Hu B, Rej RK, et al. Discovery of ERD-3111 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader with Strong Antitumor Activity. J Med Chem. 2023;66(17):12559-12585. doi:10.1021/acs.jmedchem.3c01186
5. 5.Xie B, Yin Z, Hu Z, et al. Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo. J Med Chem. 2023;66(10):6631-6651. doi:10.1021/acs.jmedchem.2c02032
6. 6.Dubash TD, Bardia A, Chirn B, et al. Modeling the novel SERD elacestrant in cultured fulvestrant-refractory HR-positive breast circulating tumor cells. Breast Cancer Res Treat. 2023;201(1):43-56. doi:10.1007/s10549-023-06998-w
7. 7.Guan J, Zhou W, Hafner M, et al. Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility. Cell. 2019;178(4):949-963.e18. doi:10.1016/j.cell.2019.06.026
8. 8.Naganuma M, Ohoka N, Tsuji G, Inoue T, Naito M, Demizu Y. Structural Optimization of Decoy Oligonucleotide-Based PROTAC That Degrades the Estrogen Receptor. Bioconjug Chem. 2023;34(10):1780-1788. doi:10.1021/acs.bioconjchem.3c00332