Figure 2 from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER&lt;sup&gt;+&lt;/sup&gt; Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance

Alan Rosen,Azadeh Cheraghchi-Bashi,Christopher J Morrow,Daniel Sutton,David I Fisher,Dawn Trueman,Elisabetta Marangoni,Elodie Montaudon,Eric T Gangl,Gareth Maglennon,Heloise Derrien,Hilary Lewis,James S Scott,Jelena Urosevic,Jennifer Moss,Jonathan Cairns,Justin P.O Lindemann,Larissa S Carnevalli,Mandy Lawson,Michelle Dupont,Mònica Sánchez-Guixé,Natalie Cureton,Neha Wali,Oona Delpuech,Pablo Morentin-Gutierrez,Pei Zhang,Radoslaw Polanski,Ricardo J Miragaia,Simon T Barry,Sladjana Gagrica,Sophie D'Arcy,Stuart C Williamson,Susan E Critchlow,Susana Ros,Teresa Klinowska,Thomas A Moss,Violeta Serra

doi:10.1158/0008-5472.24710698.v2

Abstract

Binding and activity of camizestrant in clinically relevant ERα mutations. A, The pIC50 value of fulvestrant and camizestrant to displace a fluorescent ER ligand from wild-type, D538G, Y537N, E380Q, Y537C, S463P, or Y537S mutant purified ERα ligand-binding domain. Points represent independent experiments. B, MCF7 cells expressing WT or Y537S ERα were grown for 7 days in 5% FBS. Growth inhibition was estimated with a Sytox Green assay normalized to an untreated control on day 0 (0%) and an untreated control on day 7 of treatment (100%). Data points represent the mean from two independent experiments carried out in duplicate. Fulvestrant and camizestrant inhibited the proliferation of both WT and Y537S ERα-expressing MCF7 cells in a concentration-dependent manner. The table shows pIC50 values from independent experiments. C, MCF7 cells expressing WT or Y537S ERα were treated with the indicated concentration of fulvestrant or camizestrant for 72 hours, and ERα was determined by Western blot. Fulvestrant and camizestrant showed concentration-dependent inhibition of PgR expression (normalized to an untreated control) in MCF7 cells expressing both WT and Y537S ERα. D, Camizestrant dose–response in the long-term estrogen-deprived ESR1wt PDX model, HBXF079-LTED. Statistical analysis was performed by one-tailed, unequal variance t test versus log (change in tumor volume) compared with vehicle control at the final day of treatment. E, ER degradation measured by Western blot from tumors taken at the end of the efficacy dosing period. F, In the ESR1m D538G PDX CTC-174 model, camizestrant demonstrated antitumor activity in a dose-dependent manner, with maximal antitumor activity at 10 mg/kg. Efficacy correlated with ER degradation measured by Western blot from tumors taken at the end of the efficacy dosing period. Statistical analyses were performed by one-tailed, unequal variance t test versus log (change in tumor volume) compared with vehicle control at the final day of treatment. G, ER degradation measured by Western blot from tumors taken at the end of the efficacy dosing period. NS, not significant; *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. pIC50, negative log of the IC50 (half-maximal inhibitory concentration) value when converted to mol/L.

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