ER F404L

Several oral ERa degraders were active against compound mutant models. We have identified a resistance mechanism specific to fulvestrant, that can be targeted by treatments in clinical development.

The L391F mutation resulted in an increased binding affinity for Lasofoxifene (LAS) (dAff -0.34), Giredestrant (GIR) (dAff -0.18), Elacestrant (ELA) (dAff -0.08) and Amcenestrant (AMC) (dAff -0.41), while a decreased binding affinity was observed for 4OH-Tamoxifen (TAM) (dAff 0.01), Imlunestrant (IML) (dAff 0.15), Fulvestrant (FUL) (dAff 0.43), and Camizestrant (CAM) (dAff 0.02). The study suggests that genomic variability in drug targets detectable through ctDNA may modulate therapeutic response. Preclinical models are under development to investigate the combined endocrine resistance mechanism suggested by the significant co- occurrence between ESR1 mutations in SERDs/SERMs docking sites and ESR1 hotspot mutations and provide valuable additional insights for drug development and future treatment algorithms.

We have identified a novel resistance mechanism to fulvestrant, with F404 mutations acquired in patients with pre-existing activating ESR1 mutations. F404 confers fulvestrant resistance through the loss of a pi-stacking bond and likely reduced fulvestrant binding affinity, identifying a new potential target to overcome endocrine therapy resistance.