Targeting estrogen receptor mutations and aberrant myelopoiesis in hormone resistant breast cancer

Breast cancer (BC) is the most commonly diagnosed cancer among women worldwide. In the U.S., it is the second leading cause of cancer-related mortality among women and the leading cause of cancer death among Hispanic and African American women. Approximately 70% of BCs express estrogen receptor alpha (ERalpha), which plays a central role in driving tumor development and progression. Endocrine therapy provides durable clinical benefit, as evidenced by significant reductions in local, contralateral and distant recurrence and by improvement in overall survival, with effects persisting long after treatment cessation. Despite its efficacy, development of acquired or intrinsic resistance remains a major obstacle in BC management. A key mechanism of resistance involves somatic mutations in the ESR1 gene, most commonly Y537S and D538G, which stabilize the ligand-binding domain in a constitutively-active conformation, thereby enabling ligand-independent ER signaling and diminishing effectiveness of aromatase inhibitors and tamoxifen. Until recently, fulvestrant was the only selective estrogen receptor degrader (SERD) available to counteract endocrine resistance; however, two next-generation SERDs, elacestrant and imlunestrant, have now received FDA approval. This underscores the continued need for advanced SERDs capable of effectively targeting both wild-type (WT) and mutant ERalpha while minimizing adverse effects. We have developed novel oral SERDs designed to degrade both WT and mutant ERalpha. To assess their anti-tumor activity, we evaluated these compounds in BC cell lines with and without Y537S and D538G ERalpha mutations. Treatment with our SERDs significantly reduced cell proliferation in a dose-dependent manner (P<0.01) and consistently decreased ERalpha protein levels in both WT and mutant cell lines. These effects were comparable to, or exceeded, those observed with current FDA-approved SERDs such as fulvestrant and elacestrant. Additionally, SERD treatment resulted in reduced ESR1 mRNA levels. ERalpha knockdown in BC cells abrogated SERD activity, confirming that their mechanism of action is ERalpha-dependent. Moreover, SERD JD128 demonstrated potent in vivo efficacy against MCF7-Y537S xenografts in humanized BLT-NSG-SGM3 mice (P<0.01). Analysis of the tumor immune microenvironment (TME) revealed that JD128 treatment increased T-cell infiltration compared with controls. These findings indicate that our SERDs represent promising therapeutic candidates for ERalpha-positive BC that has developed resistance to existing endocrine therapies. Furthermore, combining endocrine agents with immunotherapy may help mitigate immune suppressive myeloid populations within the TME and enhance T-cell-mediated anti-tumor responses. Funding: CIRM DISC2-14166, UCLA JCCC BC Award, Tower Cancer Res Found, Hickey Foundation, NIH/NCI U54 CA143930 CDU-UCLA JCCC Partnership, CBCRPB27IB3869, DOD BCRPBC181420.