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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2024 | Auranofin | Research

Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition

Authors: Christophe Deben, Laurie Freire Boullosa, Felicia Rodrigues Fortes, Edgar Cardenas De La Hoz, Maxim Le Compte, Sofie Seghers, Marc Peeters, Steve Vanlanduit, Abraham Lin, Krijn K. Dijkstra, Paul Van Schil, Jeroen M. H. Hendriks, Hans Prenen, Geert Roeyen, Filip Lardon, Evelien Smits

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Abstract

Background

This study explores the repurposing of Auranofin (AF), an anti-rheumatic drug, for treating non-small cell lung cancer (NSCLC) adenocarcinoma and pancreatic ductal adenocarcinoma (PDAC). Drug repurposing in oncology offers a cost-effective and time-efficient approach to developing new cancer therapies. Our research focuses on evaluating AF's selective cytotoxicity against cancer cells, identifying RNAseq-based biomarkers to predict AF response, and finding the most effective co-therapeutic agents for combination with AF.

Methods

Our investigation employed a comprehensive drug screening of AF in combination with eleven anticancer agents in cancerous PDAC and NSCLC patient-derived organoids (n = 7), and non-cancerous pulmonary organoids (n = 2). Additionally, we conducted RNA sequencing to identify potential biomarkers for AF sensitivity and experimented with various drug combinations to optimize AF's therapeutic efficacy.

Results

The results revealed that AF demonstrates a preferential cytotoxic effect on NSCLC and PDAC cancer cells at clinically relevant concentrations below 1 µM, sparing normal epithelial cells. We identified Carbonic Anhydrase 12 (CA12) as a significant RNAseq-based biomarker, closely associated with the NF-κB survival signaling pathway, which is crucial in cancer cell response to oxidative stress. Our findings suggest that cancer cells with low CA12 expression are more susceptible to AF treatment. Furthermore, the combination of AF with the AKT inhibitor MK2206 was found to be particularly effective, exhibiting potent and selective cytotoxic synergy, especially in tumor organoid models classified as intermediate responders to AF, without adverse effects on healthy organoids.

Conclusion

Our research offers valuable insights into the use of AF for treating NSCLC and PDAC. It highlights AF's cancer cell selectivity, establishes CA12 as a predictive biomarker for AF sensitivity, and underscores the enhanced efficacy of AF when combined with MK2206 and other therapeutics. These findings pave the way for further exploration of AF in cancer treatment, particularly in identifying patient populations most likely to benefit from its use and in optimizing combination therapies for improved patient outcomes.

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Gamberi T, Chiappetta G, Fiaschi T, Modesti A, Sorbi F, Magherini F. Upgrade of an old drug: Auranofin in innovative cancer therapies to overcome drug resistance and to increase drug effectiveness, Med Res Rev. 2022;42:1111–46.

Boullosa LF, Loenhout JV, Flieswasser T, Waele JD, Hermans C, Lambrechts H, Cuypers B, Laukens K, Bartholomeus E, Siozopoulou V, Vos WHD, Peeters M, Smits ELJ, Deben C. Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer, Redox Biol. 2021;42:101949.

Capparelli EV, Bricker-Ford R, Rogers MJ, McKerrow JH, Reed SL. Phase I Clinical Trial Results of Auranofin, a Novel Antiparasitic Agent, Antimicrob Agents Chemother. 2016;61(1):e01947–16.

Chaffman M, Brogden RN, Heel RC, Speight TM, Avery GS. Auranofin A preliminary review of its pharmacological properties and therapeutic use in rheumatoid arthritis. Drugs. 1984;27:378–424.CrossRefPubMed

Freire Boullosa L, Van Loenhout J, Flieswasser T, Hermans C, Merlin C, Lau HW, Marcq E, Verschuuren M, De Vos WH, Lardon F, Smits ELJ, Deben C. Auranofin Synergizes with the PARP Inhibitor Olaparib to Induce ROS-Mediated Cell Death in Mutant p53 Cancers. Antioxidants (Basel). 2023;12(3):667.CrossRefPubMed

Van Loenhout J, Freire Boullosa L, Quatannens D, De Waele J, Merlin C, Lambrechts H, Lau HW, Hermans C, Lin A, Lardon F, Peeters M, Bogaerts A, Smits E, Deben C. Auranofin and cold atmospheric plasma synergize to trigger distinct cell death mechanisms and immunogenic responses in glioblastoma. Cells. 2021;10(11):2936.CrossRefPubMedPubMedCentral

Deben C, De La Hoz EC, Compte ML, Van Schil P, Hendriks JMH, Lauwers P, Yogeswaran SK, Lardon F, Pauwels P, Van Laere S, Bogaerts A, Smits E, Vanlanduit S, Lin A. OrBITS: label-free and time-lapse monitoring of patient derived organoids for advanced drug screening. Cell Oncol (Dordr). 2023;46:299–314.CrossRefPubMed

Le Compte M, Cardenas De La Hoz E, Peeters S, Smits E, Lardon F, Roeyen G, Vanlanduit S, Prenen H, Peeters M, Lin A, Deben C. Multiparametric Tumor Organoid Drug Screening Using Widefield Live-Cell Imaging for Bulk and Single-Organoid Analysis, J Vis Exp. 2023;190:e64434.

Dijkstra KK, Monkhorst K, Schipper LJ, Hartemink KJ, Smit EF, Kaing S, de Groot R, Wolkers MC, Clevers H, Cuppen E, Voest EE. Challenges in Establishing Pure Lung Cancer Organoids Limit Their Utility for Personalized Medicine. Cell Rep. 2020;31:107588.CrossRefPubMed

10.

Le Compte M, De La Hoz EC, Peeters S, Fortes FR, Hermans C, Domen A, Smits E, Lardon F, Vandamme T, Lin A, Vanlanduit S, Roeyen G, Van Laere S, Prenen H, Peeters M, Deben C. Single-organoid analysis reveals clinically relevant treatment-resistant and invasive subclones in pancreatic cancer. NPJ Precis Oncol. 2023;7:128.CrossRefPubMedPubMedCentral

11.

Yadav B, Wennerberg K, Aittokallio T, Tang J. Searching for Drug Synergy in Complex Dose-Response Landscapes Using an Interaction Potency Model, Comput Struct. Biotechnol J. 2015;13:504–13.

12.

Bliss CI. THE TOXICITY OF POISONS APPLIED JOINTLY1. Annals of Applied Biology. 1939;26:585–615.CrossRef

13.

Loewe S. The problem of synergism and antagonism of combined drugs. Arzneimittelforschung. 1953;3:285–90.PubMed

14.

Berenbaum MC. What is synergy? Pharmacol Rev. 1989;41:93–141.PubMed

15.

Zheng S, Wang W, Aldahdooh J, Malyutina A, Shadbahr T, Tanoli Z, Pessia A, Tang J. SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets. Genomics Proteomics Bioinformatics. 2022;20:587–96.CrossRefPubMedPubMedCentral

16.

Werba G, Weissinger D, Kawaler EA, Zhao E, Kalfakakou D, Dhara S, Wang L, Lim HB, Oh G, Jing X, Beri N, Khanna L, Gonda T, Oberstein P, Hajdu C, Loomis C, Heguy A, Sherman MH, Lund AW, Welling TH, Dolgalev I, Tsirigos A, Simeone DM. Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment. Nat Commun. 2023;14:797.CrossRefPubMedPubMedCentral

17.

Prazanowska KH, Lim SB. An integrated single-cell transcriptomic dataset for non-small cell lung cancer. Sci Data. 2023;10:167.CrossRefPubMedPubMedCentral

18.

Li H, Hu J, Wu S, Wang L, Cao X, Zhang X, Dai B, Cao M, Shao R, Zhang R, Majidi M, Ji L, Heymach JV, Wang M, Pan S, Minna J, Mehran RJ, Swisher SG, Roth JA, Fang B. Auranofin-mediated inhibition of PI3K/AKT/mTOR axis and anticancer activity in non-small cell lung cancer cells. Oncotarget. 2016;7:3548–58.CrossRefPubMed

19.

Picco G, Chen ED, Alonso LG, Behan FM, Goncalves E, Bignell G, Matchan A, Fu B, Banerjee R, Anderson E, Butler A, Benes CH, McDermott U, Dow D, Iorio F, Stronach E, Yang F, Yusa K, Saez-Rodriguez J, Garnett MJ. Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR-Cas9 screening. Nat Commun. 2019;10:2198.CrossRefPubMedPubMedCentral

20.

Freire Boullosa L, Van Loenhout J, Hermans C, Lau HW, Merlin C, Marcq E, Takhsha FS, Martinet W, De Meyer GRY, Lardon F, Smits ELJ, Deben C. Optimization of the solvent and in vivo administration route of auranofin in a syngeneic non-small cell lung cancer and glioblastoma mouse model. Pharmaceutics. 2022;14(12):2761.CrossRefPubMedPubMedCentral

21.

Blodgett RC Jr, Pietrusko RG. Long-term efficacy and safety of auranofin: a review of clinical experience. Scand J Rheumatol Suppl. 1986;63:67–78.PubMed

22.

Du Y, Xin Z, Liu T, Xu P, Mao F, Yao J. Overexpressed CA12 has prognostic value in pancreatic cancer and promotes tumor cell apoptosis via NF-κB signaling. J Cancer Res Clin Oncol. 2021;147:1557–64.CrossRefPubMed

23.

Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 2011;21:103–15.CrossRefPubMed

24.

Jeon KI, Jeong JY, Jue DM. Thiol-reactive metal compounds inhibit NF-kappa B activation by blocking I kappa B kinase. J Immunol. 2000;164:5981–9.CrossRefPubMed

25.

Jeon KI, Byun MS, Jue DM. Gold compound auranofin inhibits IkappaB kinase (IKK) by modifying Cys-179 of IKKbeta subunit. Exp Mol Med. 2003;35:61–6.CrossRefPubMed

26.

Saei AA, Gullberg H, Sabatier P, Beusch CM, Johansson K, Lundgren B, Arvidsson PI, Arner ESJ, Zubarev RA. Comprehensive chemical proteomics for target deconvolution of the redox active drug auranofin. Redox Biol. 2020;32:101491.CrossRefPubMedPubMedCentral

27.

Nakaya A, Sagawa M, Muto A, Uchida H, Ikeda Y, Kizaki M. The gold compound auranofin induces apoptosis of human multiple myeloma cells through both down-regulation of STAT3 and inhibition of NF-kappaB activity. Leuk Res. 2011;35:243–9.CrossRefPubMed

28.

Dai B, Yoo SY, Bartholomeusz G, Graham RA, Majidi M, Yan S, Meng J, Ji L, Coombes K, Minna JD, Fang B, Roth JA. KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer. Can Res. 2013;73:5532–43.CrossRef

29.

Xia Y, Chen J, Yu Y, Wu F, Shen X, Qiu C, Zhang T, Hong L, Zheng P, Shao R, Xu C, Wu F, Chen W, Xie C, Cui R, Zou P. Compensatory combination of mTOR and TrxR inhibitors to cause oxidative stress and regression of tumors. Theranostics. 2021;11:4335–50.CrossRefPubMedPubMedCentral

30.

Liu X, Wang W, Yin Y, Li M, Li H, Xiang H, Xu A, Mei X, Hong B, Lin W. A high-throughput drug screen identifies auranofin as a potential sensitizer of cisplatin in small cell lung cancer. Invest New Drugs. 2019;37:1166–76.CrossRefPubMed

31.

Celegato M, Borghese C, Casagrande N, Mongiat M, Kahle XU, Paulitti A, Spina M, Colombatti A, Aldinucci D. Preclinical activity of the repurposed drug auranofin in classical Hodgkin lymphoma. Blood. 2015;126:1394–7.CrossRefPubMedPubMedCentral

32.

Natarajan D, Prasad NR, Sudharsan M, Bharathiraja P, Lakra DS. Auranofin sensitizes breast cancer cells to paclitaxel chemotherapy by disturbing the cellular redox system, Cell Biochem Funct. 2023;41(8):1305–18.

33.

Kratzke M, Scaria G, Porter S, Kren B, Klein MA. Inhibition of Mitochondrial Antioxidant Defense and CDK4/6 in Mesothelioma, Molecules. 2023;28(11):4380.

Title: Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition
Authors: Christophe Deben
Laurie Freire Boullosa
Felicia Rodrigues Fortes
Edgar Cardenas De La Hoz
Maxim Le Compte
Sofie Seghers
Marc Peeters
Steve Vanlanduit
Abraham Lin
Krijn K. Dijkstra
Paul Van Schil
Jeroen M. H. Hendriks
Hans Prenen
Geert Roeyen
Filip Lardon
Evelien Smits
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Auranofin
NSCLC
NSCLC
Biomarkers
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-024-03012-z

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