Fig. 7: ATR inhibition sensitizes ARMS PDXs to PARP1 inhibition in vivo.

a Tumor volume change of an ARMS PDX treated with AZD6738, olaparib or both compared to control (n = 4 mice per group; bottom, excess over Bliss additivity, ** P < 0.01). b Kaplan–Meier curve showing tumor doubling time after treatment. c Tumor volume change of the ARMS PDX treated with BAY 1895344 as compared to control (n = 7 mice per group; top, timeline of the drug schedule, ** P < 0.01). d Kaplan–Meier curve showing tumor doubling time after treatment. e Tumor volume change of an ARMS PDX harboring a PAX7-FOXO1 and a relapse with an additional MYCN amplification, treated with BAY 1895344 as compared to control (n = 7 mice per group; top, timeline of the drug schedule). f Kaplan–Meier curve showing tumor doubling time after treatment. g Tumor volume reduction at the endpoint of the treatment with BAY 1895344 or vehicle in a PAX7-FOXO1 ARMS PDX and a PAX7-FOXO1 MYCN amplified ARMS PDX (n = 6 mice for vehicle and n = 7 mice for BAY 1895344 treatment; P = 0.004; 0.117, respectively.) h Representative immunohistochemistry staining for cleaved Caspase3 and Ki67. Quantification of cleaved Caspase3 (i) and Ki67 (j) (n = 10 sections of 275µmx275µm; P = 0.005). k Schematic of our proposed model. PAX3-FOXO1 induces replication stress, which activates the ATR signaling pathway, promoting checkpoint activation and DNA repair. With ATR inhibitors, replication stress cannot be repaired, leading to DNA damage accumulation, mitotic arrest, and cell death. A proposed counteractive measure is the activation of the RAS-MAPK pathway, in particular FOS genes, to reduce replication stress. All statistical analyses correspond to two-sided student’s t-test; data presented as mean value ± error bars representing standard deviation. Box plots (i and j) show center line as median, box limits as upper and lower quartiles, whiskers as minimum to maximum values.