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.
Auranofin Repurposing
Drug Synergy
NSCLC and PDAC Therapy
RNAseq Biomarkers
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
22 Mar 2024
22 Mar 2024
Historique:
received:
02
01
2024
accepted:
14
03
2024
medline:
22
3
2024
pubmed:
22
3
2024
entrez:
22
3
2024
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 38515178
doi: 10.1186/s13046-024-03012-z
pii: 10.1186/s13046-024-03012-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
88Subventions
Organisme : Fonds Wetenschappelijk Onderzoek
ID : 1S27021N
Informations de copyright
© 2024. The Author(s).
Références
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.
doi: 10.2165/00003495-198427050-00002
pubmed: 6426923
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.
doi: 10.3390/antiox12030667
pubmed: 36978917
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.
doi: 10.3390/cells10112936
pubmed: 34831159
pmcid: 8616410
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.
doi: 10.1007/s13402-022-00750-0
pubmed: 36508089
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.
doi: 10.1016/j.celrep.2020.107588
pubmed: 32375033
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.
doi: 10.1038/s41698-023-00480-y
pubmed: 38066116
pmcid: 10709344
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.
Bliss CI. THE TOXICITY OF POISONS APPLIED JOINTLY1. Annals of Applied Biology. 1939;26:585–615.
doi: 10.1111/j.1744-7348.1939.tb06990.x
Loewe S. The problem of synergism and antagonism of combined drugs. Arzneimittelforschung. 1953;3:285–90.
pubmed: 13081480
Berenbaum MC. What is synergy? Pharmacol Rev. 1989;41:93–141.
pubmed: 2692037
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.
doi: 10.1016/j.gpb.2022.01.004
pubmed: 35085776
pmcid: 9801064
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.
doi: 10.1038/s41467-023-36296-4
pubmed: 36781852
pmcid: 9925748
Prazanowska KH, Lim SB. An integrated single-cell transcriptomic dataset for non-small cell lung cancer. Sci Data. 2023;10:167.
doi: 10.1038/s41597-023-02074-6
pubmed: 36973297
pmcid: 10042991
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.
doi: 10.18632/oncotarget.6516
pubmed: 26657290
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.
doi: 10.1038/s41467-019-09940-1
pubmed: 31097696
pmcid: 6522557
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.
doi: 10.3390/pharmaceutics14122761
pubmed: 36559255
pmcid: 9783082
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: 3110943
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.
doi: 10.1007/s00432-020-03447-9
pubmed: 33387040
Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 2011;21:103–15.
doi: 10.1038/cr.2010.178
pubmed: 21187859
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.
doi: 10.4049/jimmunol.164.11.5981
pubmed: 10820281
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.
doi: 10.1038/emm.2003.9
pubmed: 12754408
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.
doi: 10.1016/j.redox.2020.101491
pubmed: 32199331
pmcid: 7082630
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.
doi: 10.1016/j.leukres.2010.05.011
pubmed: 20542334
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.
doi: 10.1158/0008-5472.CAN-13-0712
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.
doi: 10.7150/thno.52077
pubmed: 33754064
pmcid: 7977446
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.
doi: 10.1007/s10637-019-00750-2
pubmed: 30825105
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.
doi: 10.1182/blood-2015-07-660365
pubmed: 26228484
pmcid: 4592277
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.
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.