Figure 5 from Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma
Authors: Ford Catriona A. , Koludrovic Dana , Centeno Patricia P. , Foth Mona , Tsonou Elpida , Vlahov Nikola , Sphyris Nathalie , Gilroy Kathryn , Bull Courtney , Nixon Colin , Serrels Bryan , Munro Alison F. , Dawson John C. , Carragher Neil O. , Pavet Valeria , Hornigold David C. , Dunne Philip D. , Downward Julian , Welch Heidi C.E. , Barry Simon T. , Sansom Owen J. , Campbell Andrew D. 
Published: February 2025

<p>Therapeutic targeting of MEK1/2 and the RAC1 effector p110β has marked therapeutic efficacy in melanoma <i>in vivo</i>. <b>A,</b> Left, Kaplan–Meier overall survival of mice harboring WM266.4 subcutaneous xenografts treated with vehicle (<i>n</i> = 5; median survival, 33 days), AZD6244 (<i>n</i> = 5; median survival, 49 days), AZD8186 (<i>n</i> = 5; median survival, 44 days), or AZD6244/AZD8186 (<i>n</i> = 5; median survival, 128 days). <i>P</i> values calculated using the log-rank (Mantel–Cox) test: vehicle vs. AZD6244, <i>P</i> = 0.2269; vehicle vs. AZD8186, <i>P</i> = 0.3091; vehicle vs. AZD6244/AZD8186, <i>P</i> = 0.0017 and AZD6244 vs. AZD6244/AZD8186, <i>P</i> = 0.0064. Middle, relative change in tumor volume of WM266.4 xenografts over the first 21 days of indicated treatment. Vehicle (<i>n</i> = 5), AZD6244 (<i>n</i> = 4), AZD8186 (<i>n</i> = 5), AZD6244/AZD8186 (<i>n</i> = 5). <i>P</i> values calculated by one-way ANOVA corrected for multiple comparisons (Tukey). Right, longitudinal growth of individual WM266.4 xenografts treated with vehicle (<i>n</i> = 5) vs. AZD6244 (<i>n</i> = 5), AZD8186 (<i>n</i> = 5), or AZD6244/AZD8186 (<i>n</i> = 5). <b>B,</b> Left, Kaplan–Meier overall survival of BRAF PTEN mice treated with vehicle (<i>n</i> = 8; median survival, 12.5 days), AZD6244 (<i>n</i> = 8; median survival, 74.5 days), AZD8186 (<i>n</i> = 8; median survival, 15 days), or AZD6244/AZD8186 (<i>n</i> = 8; median survival, 139 days). <i>P</i> values calculated using the log-rank (Mantel–Cox) test: vehicle vs. AZD6244, <i>P</i> = 0.009550; vehicle vs. AZD8186, <i>P</i> = 0.437704; vehicle vs. AZD6244/AZD8186, <i>P</i> = 0.000012 and AZD6244 vs. AZD6244/AZD8186, <i>P</i> = 0.004813. Middle, relative change in tumor volume of BRAF PTEN mice over the first 7 days of indicated treatment. Vehicle (<i>n</i> = 8), AZD6244 (<i>n</i> = 7), AZD8186 (<i>n</i> = 8), AZD6244/AZD8186 (<i>n</i> = 11). <i>P</i> values calculated by one-way ANOVA corrected for multiple comparisons (Tukey). Right, longitudinal growth of individual tumors from vehicle-treated (<i>n</i> = 8) vs. AZD6244-treated (<i>n</i> = 7), AZD8186-treated (<i>n</i> = 8), and AZD6244/AZD8186-treated (<i>n</i> = 11) BRAF PTEN cohorts. Note that the BRAF PTEN vehicle- and AZD6244-treated cohort data are also used in <a href="#fig2" target="_blank">Figs. 2</a> and <a href="#fig3" target="_blank">3</a>. <b>C,</b> Left, representative H&E staining and IHC against pERK1/2 (Thr202/Tyr204), pRPS6 (Ser235/Ser236), pRPS6 (Ser240/Ser244), cyclin D1, and p21 in BRAF PTEN mice treated with indicated treatment. Right, representative H&E staining and IHC against cyclin D1 and p21 in tumor sections from BRAF PTEN PREX2 mice treated with vehicle or AZD6244. <b>D,</b> Top, Kaplan–Meier overall survival of BRAF PTEN PREX2-GD mice treated with vehicle (<i>n</i> = 8; median survival, 11 days), AZD6244 (<i>n</i> = 8; median survival, 100.5 days), AZD8186 (<i>n</i> = 4; median survival, 7 days), or AZD6244/AZD8186 (<i>n</i> = 7; median survival, 87 days). <i>P</i> values calculated using the log-rank (Mantel–Cox) test: vehicle vs. AZD6244, <i>P</i> = 0.00008; vehicle vs. AZD8186, <i>P</i> = 0.73075; vehicle vs. AZD6244/AZD8186, <i>P</i> = 0.00328 and AZD6244 vs. AZD6244/AZD8186, <i>P</i> = 0.11574. Bottom, longitudinal growth of individual tumors from vehicle-treated (<i>n</i> = 7) vs. AZD6244-treated (<i>n</i> = 6), AZD8186-treated (<i>n</i> = 3), and AZD6244/AZD8186-treated (<i>n</i> = 7) BRAF PTEN PREX2-GD cohorts. NB: the BRAF PTEN PREX2-GD vehicle- and AZD6244-treated cohort data are also used in <a href="#fig2" target="_blank">Fig. 2C</a>. <b>E,</b> Schematic of proposed proproliferative relationship between p110β and PREX2 in melanoma <i>in vivo</i>. GPCR, G-protein–coupled receptor; PIP<sub>3</sub>, phosphatidylinositol-3,4,5-trisphosphate; RTK, receptor tyrosine kinase. [<b>E,</b> Created in BioRender. Campbell, A. (2025), <a href="https://BioRender.com/a89p130" target="_blank">https://BioRender.com/a89p130</a>.]</p>