Figure 2 from The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER<sup>+</sup> Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance
Authors: Lawson Mandy , Cureton Natalie , Ros Susana , Cheraghchi-Bashi Azadeh , Urosevic Jelena , D'Arcy Sophie , Delpuech Oona , DuPont Michelle , Fisher David I. , Gangl Eric T. , Lewis Hilary , Trueman Dawn , Wali Neha , Williamson Stuart C. , Moss Jennifer , Montaudon Elodie , Derrien Heloise , Marangoni Elisabetta , Miragaia Ricardo J. , Gagrica Sladjana , Morentin-Gutierrez Pablo , Moss Thomas A. , Maglennon Gareth , Sutton Daniel , Polanski Radoslaw , Rosen Alan , Cairns Jonathan , Zhang Pei , Sánchez-Guixé Mònica , Serra Violeta , Critchlow Susan E. , Scott James S. , Lindemann Justin P.O. , Barry Simon T. , Klinowska Teresa , Morrow Christopher J. , Carnevalli Larissa S. 
Published: March 2024

<p>Binding and activity of camizestrant in clinically relevant ERα mutations. <b>A,</b> The pIC<sub>50</sub> 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>B,</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 pIC<sub>50</sub> values from independent experiments. <b>C,</b> 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. <b>D,</b> Camizestrant dose–response in the long-term estrogen-deprived <i>ESR1</i>wt PDX model, HBXF079-LTED. Statistical analysis was performed by one-tailed, unequal variance <i>t</i> test versus log (change in tumor volume) compared with vehicle control at the final day of treatment. <b>E,</b> ER degradation measured by Western blot from tumors taken at the end of the efficacy dosing period. <b>F,</b> In the <i>ESR1</i>m 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 <i>t</i> test versus log (change in tumor volume) compared with vehicle control at the final day of treatment. <b>G,</b> ER degradation measured by Western blot from tumors taken at the end of the efficacy dosing period. NS, not significant; *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001; ****, <i>P</i> < 0.0001. pIC<sub>50</sub>, negative log of the IC<sub>50</sub> (half-maximal inhibitory concentration) value when converted to mol/L.</p>