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. 2020 Sep 1;70(4):743–760. doi: 10.1136/gutjnl-2019-319970

Figure 7.

Figure 7

ATM inhibition sensitises PDAC patient-derived xenografts to PAD therapy. (A) Schematic representation of the subcutaneous assays shown in (C), (D) and (H) with treatment administration schedule. (B) Clinical characteristics and pathogenic mutations of patient-derived xenografts (PDXs) and of corresponding PDAC patients. Only class IV and V mutations are shown. (C) Waterfall plot showing best response of 10 PDXs to a combination of an ATM inhibitor (AZD0156, 2.25 mg/kg) and olaparib (50 mg/kg), VE-822 (20 mg/kg) and CC-115 (2.5 mg/kg) (PAD, PARPi/ATRi/DNA-PKi). Every bar represents one PDX. The horizontal dotted lines represent limits of progressive disease (PD, +20%), stable disease (SD, between +20% and −30%), and partial response (PR, −30%). (D) Time-dependent development (over the course of 16 days) of subcutaneously engrafted tumours arising from Panc354 PDXs treated or not (respectively, dashed lines and solid lines) with a combination of AZD0156 and PAD as in (C), with representative macroscopic images. Scale bars represent 5 mm. (E) Immunohistochemistry staining for H2AX p-S139 and cleaved caspase-3 (CC3), and (F) quantifications of H2AX p-S139-positive cells and (G) of CC3-positive surface in resected tumours from subcutaneous assay shown in (D). Scale bars represent 75 µm. (H) Time-dependent development (over the course of 16 days) of subcutaneously engrafted tumours arising from Panc163 PDXs treated or not (respectively, dashed lines and solid lines) with a combination of AZD0156 and PAD as in (C), with representative macroscopic images. Scale bars represent 5 mm. (I) Immunohistochemistry staining for H2AX p-S139 and cleaved caspase-3 (CC3), and (J) quantifications of H2AX p-S139-positive cells and (K) of CC3-positive surface in resected tumours from subcutaneous assay shown in (H). Scale bars represent 75 µm. (L) Schematic representation of the toxicity assay shown in (M and N) with treatment administration schedule. (M) Body weight progression (over the course of 14 days) and (N) complete blood count of C57BL/6J mice enrolled in the toxicity assay and treated with AZD0156 (2.25 mg/kg) and PAD (olaparib (50 mg/kg), VE-822 (20 mg/kg) and CC-115 (2.5 mg/kg)) as in (L). The horizontal red dashed line represents the weight loss ethical endpoint (−20%). DSB, double-strand break; PLT, platelets; RBC, red blood cells; TNM, tumour, nodes, metastasis classification; Veh, vehicle; WBC, white blood cells. *, p<0.05; **, p<0.01; ***, p<0.001.