Illustration of the mechanism of action of Elacetrant

Elacestrant is an oral selective estrogen receptor degrader (SERD). Its mechanism of action has breakthrough significance in the treatment of ER-positive, HER2-negative breast cancer. When estrogen receptor ER is expressed on the surface of cancer cells, estrogen binds to it and activates downstream signals to promote cell division and proliferation, allowing the cancer to continue to grow. Especially in tumors with mutations in the ESR1 gene, even if conventional endocrine therapy blocks estrogen production, the mutated receptor continues to be activated, leading to drug resistance.

However, the advantage of elastran is that it not only binds to ER receptors, but can also induce conformational changes in the receptors and guide their degradation through the intracellular proteasome pathway, thereby reducing the number of ER receptors. This "degradation" mechanism goes beyond simply blocking receptor binding with traditional estrogen antagonists such as tamoxifen or aromatase inhibitors, and is therefore particularly effective in cancer cells that are ER+ but ESR1 mutation-positive.

Specifically, after entering the blood, elastran binds with high affinity ERα, inducing changes in the tertiary structure of the receptor, marking it as a degradation target and being cleared by the ubiquitin‑proteasome system, thereby reducing the number of surviving receptors. This means that even if estrogen is still secreted in the body, it cannot continue to activate proliferation signals due to the lack of receptors. This mechanism can still play a role after multiple rounds of endocrine treatment failure, especially for ESR1 mutant receptors with efficient degradation activity.

For for patients with ER+ HER2− advanced breast cancer who fail CDK4/6 inhibitors combined with endocrine therapy, elastran is a targeted and optimized treatment strategy. Its oral administration method also makes the drug more patient-compliant and suitable for long-term treatment management. Overall, elastran cuts off the stimulation of cancer cells by estrogen at the source by blocking and destroying the ER receptor, providing a new and precise and effective direction for drug-resistant endocrine therapy.

References:https://www.drugs.com/mtm/elacestrant.html