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

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© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Genetic and chemical ATM inactivation leverages HRDness in human PDAC. (A) Viability assay analysis of olaparib treatment in ATM^+/+, ATM^+/Δ and ATM^Δ/Δ MIA PaCa-2 cells. (B) Schematic representation of viability assay shown in (C). (D) Schematic representation of the subcutaneous assay shown in (E) with treatment administration schedule. (E) Time-dependent development (over the course of 24 days) of subcutaneously engrafted tumours arising from ATM^+/Δ MIA PaCa-2 cells treated (dotted line) or not (solid line) with a combination of olaparib (50 mg/kg), VE-822 (20 mg/kg) and, CC-115 (2.5 mg/kg) (PAD, PARPi/ATRi/DNA-PKi). (F) Immunohistochemistry staining for H2AX p-S139 and (G) quantifications of H2AX p-S139-positive cells in resected tumours from subcutaneous assay shown in (E). Scale bars represent 100 µm. (H) Viability assay analysis of olaparib treatment in ATM^+/+ MIA PaCa-2 cells treated or not with an ATM inhibitor (AZD0156). (I) Schematic representation of viability assay shown in (J). (J) Viability assay on ATM^+/+ MIA PaCa-2 cells treated or not with an ATM inhibitor (AZD0156 or KU-60019) and with varying combinations of olaparib (PARPi), VE-822 (ATRi), and CC-115 (DNA-PKi). White solid lines delimit the area with a cell viability below 70%. (K) Schematic representation of the subcutaneous assay shown in (L) with treatment administration schedule. (L) Time-dependent development (over the course of 25 days) of subcutaneously engrafted tumours arising from ATM^+/+ MIA PaCa-2 cells treated or not with PAD as in (E) (respectively, grey and black squares) and/or an ATM inhibitor (2.25 mg/kg AZD0156; respectively, purple and blue triangles). (M) Quantification of tumour weight of resected tumours from subcutaneous assay shown in (L). (N) Immunohistochemistry staining for H2AX p-S139 and O), quantification of H2AX p-S139-positive cells in resected tumours from subcutaneous assay shown in (L). Scale bars represent 100 µm. (P) Body weight progression (over the course of 25 days) of athymic Nude-Foxn1^nu mice enrolled in the subcutaneous assay shown in (L). The horizontal red dashed line represents the weight loss ethical endpoint (−20%). Veh, vehicle. **, p<0.01; ***, p<0.001; ****, p<0.0001; a and b, p<0.0001 when compared with ATM^+/+ MIA PaCa-2 cells, §, p<0.05 when compared with ATM^+/Δ MIA PaCa-2 cells (A).