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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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Customised screening identifies synergistically operating targets in ATM-deficient PDAC. (A) Frequency of DNA repair gene alterations (n=60) in primary pancreatic ductal adenocarcinomas (PDAC) (n=670) from three PDAC sequencing data sets using cBioPortal. Of note, no MLH1 alteration was found. (B) Mini drug viability assay screening performed on Atm^+/+; LSL-Kras^G12D/+; Ptf1a^Cre/+ (KC) and Atm^fl/fl; LSL-Kras^G12D/+; Ptf1a^Cre/+ (AKC) cells with increasing doses of 45 drugs. (C) Contingency table comparing drug target and AKC-specific effect. Schematic representations of (D) drug synergism, (E) synergistic treatment and (F) drug synergism using zero interaction potency (ZIP) model. (G), (J), (M) and (P), Schematic representation of viability assays and colony formation assays respectively shown in (H–I), (K–L), (N–O) and Q–R). (H), (K), (N) and (Q), viability assay and (I), (L), (O) and (R), colony formation assay on KC and AKC cells treated 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% (H), (K), (N) and (Q). Drug synergism analysis of the viability assay shown in (Q) using (S) a three-agent model comparing zero-interaction surfaces with and without PARPi fixed at 1 µM and (T) MuSyC (multidimensional synergy of combinations) model separating potency (α; synergistic effect when α>0, antagonistic effect when α<0) from efficacy (β; synergistic effect when β>0, antagonistic effect when β<0). 5FU, 5-fluorouracil; AZD, AZD7762; CARB, carboplatin; CIS, cisplatin; DABR, dabrafenib; DECI, decitabine; DORS, dorsomorphin; DOXO, doxorubicin; DSB, double-strand break; ERLO, erlotinib; ETO, etoposide; EVER, everolimus; GEM, gemcitabine; IRI, irinotecan; JAK, JAK inhibitor I; LAPA, lapatinib; METF, metformin; MIR, mirin; MITO, mitomycin C; MK, MK-1775; MLN, MLN4924; NAC, N-acetylcystein; NIRA, niraparib; NU, NU7026; OLA, olaparib; OXA, oxaliplatin; PACL, paclitaxel; PALB, palbociclib; PD, PD0325901; PD1, PD-1/PD-L1 inhibitor 1; PEME, pemetrexed; SB, SB431542; SELU, selumetinib; SORA, sorafenib; SUNI, sunitinib; TIV, tivantinib; TRAM, trametinib; Veh, vehicle; VENE, venetoclax; VINO, vinorelbine; VORI, vorinostat; WORT, wortmannin.