What is the mechanism of Elacestrant?

Elacestrant is a novel therapeutic agent belonging to a class of drugs known as selective estrogen receptor degraders (SERDs). Understanding the mechanism of Elacestrant provides insight into its potential as a treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

At the molecular level, Elacestrant functions by targeting the estrogen receptor (ER), a protein that plays a critical role in the growth and proliferation of certain types of breast cancer cells. Estrogen receptors, when bound by estrogen, activate transcription of genes that drive cell division and survival. In cases where breast cancer cells are ER-positive, blocking or degrading these receptors can significantly impede tumor growth.

Elacestrant exhibits its therapeutic effects through a dual mechanism: antagonism and degradation of the estrogen receptor.

Firstly, Elacestrant acts as an estrogen receptor antagonist. By binding competitively to the estrogen receptor, it prevents estrogen from attaching to the receptor. This blockade inhibits the estrogen-induced transcriptional activity that promotes cancer cell growth. Unlike traditional selective estrogen receptor modulators (SERMs) such as tamoxifen, which can have mixed agonist/antagonist effects depending on the tissue, Elacestrant ensures a more consistent antagonistic effect on the estrogen receptor in breast tissue.

Secondly, and more distinctively, Elacestrant induces the degradation of the estrogen receptor. Upon binding to the ER, Elacestrant changes the receptor’s conformation, marking it for recognition by the cell's quality control machinery. This leads to the recruitment of ubiquitin ligases, enzymes that tag the receptor with ubiquitin molecules. Ubiquitination targets the receptor for degradation via the proteasome pathway, a protein complex responsible for breaking down unneeded or damaged proteins within the cell. Degradation of the estrogen receptor results in a reduced number of functional receptors available on breast cancer cells, thereby diminishing the cell's ability to respond to estrogen and further curtailing tumor proliferation.

An important aspect of Elacestrant's mechanism is its ability to overcome resistance that often develops with other endocrine therapies. For instance, mutations in the estrogen receptor gene (ESR1), which can arise during treatment with aromatase inhibitors or SERMs, often lead to a form of the receptor that is constitutively active or less responsive to traditional therapies. Elacestrant has shown efficacy against these mutant forms of the receptor, offering a promising option for patients who have experienced disease progression on other endocrine therapies.

In summary, Elacestrant's mechanism of action involves both antagonizing and degrading the estrogen receptor, thereby hindering the growth of HR+/HER2- breast cancer cells. Its ability to target and degrade mutant forms of the estrogen receptor further underscores its potential as an effective treatment for advanced or metastatic breast cancer, especially in cases where resistance to other endocrine therapies has developed. This dual mechanism sets Elacestrant apart and highlights its promise in improving outcomes for patients battling hormone receptor-positive breast cancer.