Figure 4 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>Genetic targeting of p110β and its interaction with RAC1 sensitizes to MEK1/2 inhibition <i>in vitro</i> and <i>in vivo.</i><b>A,</b> Left, flow cytometry–based cell-cycle profiling of WM266.4 cells following indicated 24-hour treatment. Right, proportion of WM266.4 cells in G<sub>1</sub>/S at 24 hours. <i>n</i> = 3 independent experiments. <i>P</i> values calculated by one-way ANOVA corrected for multiple comparisons (Tukey). <b>B,</b> Left, flow cytometry–based cell-cycle profiling of A375 cells following indicated 24 hours treatment. Middle, proportion of A375 cells in G<sub>1</sub>/S at 24 hours. Right, proportion of subdiploid A375 cells at 24 hours. <i>n</i> = 4 independent experiments. <i>P</i> values calculated by one-way ANOVA corrected for multiple comparisons (Tukey). <b>C,</b> Left, Kaplan–Meier overall survival of BRAF PTEN mice treated with vehicle or AZD6244. BRAF PTEN + vehicle (<i>n</i> = 8; median survival, 12.5 days) vs. BRAF PTEN + AZD6244 (<i>n</i> = 8; median survival, 74.5 days), <i>P</i> = 0.0096; BRAF PTEN PIK3CB-mut + vehicle (<i>n</i> = 4; median survival, 11.5 days) vs. BRAF PTEN PIK3CB-mut + AZD6244 (<i>n</i> = 7; median survival, 83 days), <i>P</i> = 0.0082; BRAF PTEN + AZD6244 (<i>n</i> = 8; median survival, 74.5 days) vs. BRAF PTEN PIK3CB-mut + AZD6244 (<i>n</i> = 7; median survival, 83 days), <i>P</i> = 0.1643. <i>P</i> values calculated using the log-rank (Mantel–Cox) test. Middle, longitudinal growth of individual tumors from vehicle-treated (<i>n</i> = 8) vs. AZD6244-treated (<i>n</i> = 7) BRAF PTEN cohorts and vehicle-treated (<i>n</i> = 5) vs. AZD6244-treated (<i>n</i> = 7) BRAF PTEN PIK3CB-mut cohorts. Right, relative change in tumor volume over the first 7 days of indicated treatment. BRAF PTEN + vehicle (<i>n</i> = 8), BRAF PTEN + AZD6244 (<i>n</i> = 7), BRAF PTEN PIK3CB-mut + vehicle (<i>n</i> = 5), BRAF PTEN PIK3CB-mut + AZD6244 (<i>n</i> = 6); <i>P</i> values calculated by one-way ANOVA corrected for multiple comparisons (Tukey). Center line, mean. Note that the BRAF PTEN treatment datasets are reproduced from <a href="#fig2" target="_blank">Fig. 2A</a> and <a href="#fig2" target="_blank">C</a>. <b>D,</b> Left, relative confluence of WM266.4 <i>PIK3CB</i><sup>KO</sup> cells treated with indicated treatments over the 96-hour period. Representative of a minimum of three independent experiments and three technical replicates. Data, mean ± SEM (confluence relative to starting point). Right, relative change in confluence of WM266.4 <i>PIK3CB</i><sup>KO</sup> cells over the indicated 96-hour period. Center line, mean. <i>P</i> values calculated by one-way ANOVA corrected for multiple comparisons (Tukey).</p>