Figure 4 from <i>KRAS</i> Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition
Authors: Fey Sigrid K. , Najumudeen Arafath K. , Watt Dale M. , Millett Laura M. , Ford Catriona A. , Gilroy Kathryn , Simpson Rosalin J. , McLay Kathy , Upstill-Goddard Rosanna , Chang David , Clark William , Nixon Colin , Birch Joanna L. , Barry Simon T. , Morton Jennifer P. , Campbell Andrew D. , Sansom Owen J. 
Published: January 2025

<p>Late-stage intervention with MEK1/2 inhibition improves survival of KPC <i>Kras</i><sup>G12D/fl</sup> mice. <b>A,</b> Experimental schematic. KPC <i>Kras</i><sup>G12D/+</sup> and KPC <i>Kras</i><sup>G12D/fl</sup> mice were palpated for tumor burden, with palpable tumor burden confirmed by ultrasound imaging, with mice treated continuously from the following day with either vehicle or AZD6244. Tumor growth was monitored by ultrasound imaging once weekly to clinical endpoint. <b>B,</b> Relative volume of pancreatic tumors arising in KPC <i>Kras</i><sup>G12D/+</sup> and KPC <i>Kras</i><sup>G12D/fl</sup> mice treated with either vehicle control or AZD6244 from palpable tumor and aged to clinical endpoint. Tumor volume was measured once weekly by high-resolution ultrasound imaging. Each line represents an individual mouse of the indicated genotype and treatment. KPC <i>Kras</i><sup>G12D/fl</sup> vehicle, <i>n</i> = 6; KPC <i>Kras</i><sup>G12D/fl</sup> AZD6244, <i>n</i> = 7; KPC <i>Kras</i><sup>G12D/+</sup> vehicle, <i>n</i> = 6; KPC <i>Kras</i><sup>G12D/+</sup> AZD6244, <i>n</i> = 4. FC, fold change. <b>C,</b> Change of tumor volume (mm<sup>3</sup>) of KPC <i>Kras</i><sup>G12D/+</sup> and KPC <i>Kras</i><sup>G12D/fl</sup> mice treated with either vehicle control or AZD6244 from palpable tumor between initial ultrasound measurement and a secondary ultrasound measurement (between 6 and 13 days later). Plot represents Log<sub>2</sub>(FC) of tumor volume between first and second measurements for the full treatment cohort when more than one imaging session was possible. KPC <i>Kras</i><sup>G12D/fl</sup> vehicle, <i>n</i> = 5; KPC <i>Kras</i><sup>G12D/fl</sup> AZD6244, <i>n</i> = 7; KPC <i>Kras</i><sup>G12D/+</sup> vehicle, <i>n</i> = 4; KPC <i>Kras</i><sup>G12D/+</sup> AZD6244, <i>n</i> = 4. <b>D,</b> Kaplan–Meier survival curves for KPC <i>Kras</i><sup>G12D/+</sup> and KPC <i>Kras</i><sup>G12D/fl</sup> mice treated with vehicle or AZD6244, as indicated, from palpable tumor burden and aged to clinical endpoint. KPC <i>Kras</i><sup>G12D/fl</sup> vehicle, <i>n</i> = 5; KPC <i>Kras</i><sup>G12D/fl</sup> AZD6244, <i>n</i> = 8; KPC <i>Kras</i><sup>G12D/+</sup> vehicle, <i>n</i> = 6; KPC <i>Kras</i><sup>G12D/+</sup> AZD6244, <i>n</i> = 5. MS, median survival. <b>E,</b> Representative hematoxylin and eosin images of tumors from KPC <i>Kras</i><sup>G12D/+</sup> and KPC <i>Kras</i><sup>G12D/fl</sup> mice treated with vehicle or AZD6244, as indicated, from palpable tumor burden and aged until clinical endpoint. Representative of five mice per group. Scale bar, 500 μm. <b>F,</b> Left, volcano plot for differentially expressed genes of KPC <i>Kras</i><sup>G12D/+</sup> tumors treated with vehicle or AZD6244 from palpable tumor burden to clinical endpoint. Right, volcano plot for differentially expressed genes of KPC <i>Kras</i><sup>G12D/fl</sup> tumors treated with vehicle or AZD6244 from palpable tumor burden to clinical endpoint. Red, significantly altered genes. <b>G,</b> Schematic representing relative impact of WT Kras deletion upon tumur outgrowth and therapeutic responses from KPC <i>Kras</i><sup>G12D/+</sup> and <i>Kras</i><sup>G12D/fl</sup> comparison.</p>