Figure 3: Cancer-associated ATM mutations predict MEK inhibitor sensitivity.
From: MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated
(a) Representative dose–response curves for sensitive and resistant lung cancer cell lines treated with trametinib for 5 days and normalized to vehicle control. Error bars indicate s.d.’s (n=3). KRAS/BRAF genotypes for indicated cell lines: NCI-H460: KRAS-Q61H; NCI-H322: None; NCI-H23: KRAS-G12C; NCI-H1666: BRAF-G466V; NCI-H157: KRAS-G12R. (b) Sensitivity of indicated 16 cell lines to trametinib. Shown is the area under curve (AUC) derived from dose–response experiments as in a. When applicable, the heterozygous (het) or homozygous (hom) mutational status of ATM is indicated above the bars and mutational status for selected genes is indicated below. Error bars indicate s.d.’s (n=3). (c) Area under curve values derived from dose–response experiments with TAK-733 and trametinib for 16 lung cancer cell lines. (d) Sensitivity of lung cancer cell lines in the Cancer Cell Line Encyclopedia (CCLE) to the MEK inhibitor AZD6244 (selumetinib). High activity area score (area above the curve24=AAS) indicates drug sensitivity. Each circle indicates a single cell line and cell lines are grouped according to genotype (WT=wild type for K-Ras, H-Ras, N-Ras, BRAF, c-RAF and ATM; ATM=ATM mutant; RAS=K-Ras, H-Ras or N-Ras mutant). ATM mutations are labelled according to PolyPhen predictions (damaging >0.9, neutral <0.9). Black bar indicates mean AAS. **P<0.01, ****P<0.0001, NS=not significant, two-sided t-test compared with WT group. (e) Analysis as in d for ARID1A mutant or wild-type cell lines for sensitivity to indicated MEK inhibitors. NS=not significant, two-sided t-test. (f) Analysis of ATM or RAS/BRAF mutant cell lines for response to drugs (n=20) in CCLE data set. Indicated is the P value for each drug.
