Fig. 2: RAS dependency characterization and associations to MEK inhibitor responsivity.
From: Diffusion kernel-based predictive modeling of KRAS dependency in KRAS wild type cancer cell lines
a Proportion of gene-dependent cell lines in the four subgroups of wild type cancer cell lines. The numbers above the columns indicate the absolute number of dependent cell lines. b Total number of co-dependencies for each gene. c Validation of the elaborated KRAS dependent and independent subgroups. After dividing the cell lines into KRAS dependent and independent using the Achilles Project CRISPR data, we verified the existence of the two subgroups in data of the DRIVE (RNAi) and the Score Project (CRISPR). Cell lines classified as KRAS dependent in the Achilles data exhibited a significantly higher dependency in both screens (Wilcox Test; DRIVE: p = 4,6 * 10−10, n = 342; Score: p = 2.1 * 10−4, n = 124). d Proportions of the different entities in the KRASwt group (inner circle) and the proportion of KRAS-dependent cell lines in each entity with indicated absolute numbers (outer circle). Only entities with at least ten cell lines were included in the figure. In absolute numbers, lung tumors were the most represented entity among KRAS dependent cell lines, followed by skin tumors. Overall, the group is very heterogeneous without one entity clearly dominating. e Characterization of MEK-inhibitors sensitivity in KRASwt cancer cell lines with dependent (blue, wt (dependent)) independent (purple, wt (independent)) status and as a reference KRASmut cases (green, mut). The symbols above the brackets refer to the following significance codes: *** < 0.001; ** < 0.01; * < 0.05]; ‘n.s.’ > 0.05. In the overall comparison between the three groups, KRASwt cell lines with KRAS dependency are significantly more responsive to MEK inhibitors (lower AUC) than KRASwt independent group, but for some inhibitors less responsive than the KRASmut cell lines (Wilcox Test: Trametinib: (1) p = 4.6 * 10−4 (n = 183), (2) p = 7.4 * 10−3 (n = 113); Ulixertinib: (1) p = 4.1 * 10−3 (n = 183), (2) p = 9.5 * 10−2 (n = 112); VX-11e: (1) p = 4.9 * 10−4 (n = 178), (2) p = 9.7 * 10−2 (n = 111); ERK_6604: (1) p = 1.8 * 10−4 (n = 179), (2) p = 1.3 * 10−1 (n = 111)). For further compounds of CCLE, GDSC1, and GDSC2 see also Supplementary Fig. 1. Box plot annotation (c, e): 25th percentile (box bottom), 75th percentile (box top), median (box center), whiskers top/bottom ±1.5 × interquartile range, outliers are shown as dots.
