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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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A multi-layered mechanism secures PARPi resistance in unstable PDAC. (A) Representative images of AKC and R-AKC cell lines. Scale bars represent 200 µm. (B) qRT-PCR analysis of epithelial-mesenchymal transition genes expression in AKC and R-AKC cells. (C) Western blot analysis and (D) quantification of CDH1, VIM and CDH2 levels of AKC and R-AKC cells. (E) Transwell migration assay performed with AKC and R-AKC cells. (F) Mini drug viability assay screening performed on R-AKC cells with increasing doses of 45 drugs. (G) Viability assay analysis on R-AKC cells treated or not with a combination of olaparib (1 µM), VE-822 (20 nM) and CC-115 (30 nM) (PAD, PARPi/ATRi/DNA-PKi) and a MDR1 inhibitor (elacridar). (H) qRT-PCR analysis of Lig1 gene expression in AKC and R-AKC cells. (I) Viability assay analysis on shScramble- (shScr) and shLig1-harbouring R-AKC cells treated with varying combinations of PAD and either a MDR1 inhibitor (elacridar) or a CYP3A/MDR1 inhibitor (clarithromycin). (J) Schematic representation of multi-layered PARP resistance in R-AKC cells. 5FU, 5-fluorouracil; AZD, AZD7762; CARB, carboplatin; CIS, cisplatin; DABR, dabrafenib; DECI, decitabine; DORS, dorsomorphin; DOXO, doxorubicin; DSB, double-strand break; EMT, epithelial-mesenchymal transition; ERLO, erlotinib; ETO, etoposide; EVER, everolimus; GEM, gemcitabine; GST, glutathione S-transferase; HR, homologous recombination; 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. *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001.