Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors
Background: The addition of CDK4/6 inhibitors (CDK4/6i) to endocrine therapy has significantly improved progression-free survival, leading to their approval and integration into the treatment regimen for metastatic breast cancer. As these inhibitors are increasingly used for advanced estrogen receptor-positive (ER+) breast cancer, understanding resistance mechanisms and their impact on subsequent therapies is crucial. Given ER’s pivotal role in driving ER+ breast cancer growth, it is essential to explore how prior exposure to CDK4/6i affects ER signaling and the relevance of ER-targeted therapies. This study aimed to assess the anti-tumor activity of elacestrant, a novel oral selective estrogen receptor degrader (SERD), in preclinical models of CDK4/6i resistance.
Methods: Elacestrant was tested both as a single agent and in combination with alpelisib or everolimus in various in vitro models and patient-derived xenografts representing acquired and “de novo” CDK4/6i resistance.
Results: Elacestrant effectively inhibited growth in cells resistant to all three approved CDK4/6 inhibitors (palbociclib, abemaciclib, ribociclib), regardless of ESR1 mutation status. Additionally, elacestrant alone and in combination inhibited the growth of patient-derived xenografts from patients previously treated with a CDK4/6i or those with de novo resistance. Despite distinct alterations in cell cycle modulators in resistant lines, elacestrant’s anti-tumor activity remained unaffected. Elacestrant was found to downregulate several key cell cycle regulators and halt cell cycle progression both in vitro and in vivo.
Conclusions: Our study shows that ER signaling remains crucial for tumor growth in breast cancer cells even after CDK4/6i treatment. Elacestrant effectively targets this ER-dependent growth despite mechanisms of CDK4/6i resistance such as Rb loss, CDK6 overexpression, and upregulation of cyclin E1 and E2F1. These findings support the evaluation of elacestrant in patients with CDK4/6i resistance and suggest that it could serve as a foundational component for developing combination therapies to address resistance.