Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer
Abstract Background Adrenocortical cancer (ACC) is a rare and aggressive cancer with dismal 5-year survival due to a lack of effective treatments. We aimed to identify a new effective combination of drugs and investigated their synergistic efficacy in ACC preclinical models. Methods A quantitative h...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02464-5 |
| _version_ | 1811208648804794368 |
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| author | Dipranjan Laha Robert R.C. Grant Prachi Mishra Myriem Boufraqech Min Shen Ya-Qin Zhang Matthew D. Hall Martha Quezado Michelly Sampaio De Melo Jaydira Del Rivero Martha Zeiger Naris Nilubol |
| author_facet | Dipranjan Laha Robert R.C. Grant Prachi Mishra Myriem Boufraqech Min Shen Ya-Qin Zhang Matthew D. Hall Martha Quezado Michelly Sampaio De Melo Jaydira Del Rivero Martha Zeiger Naris Nilubol |
| author_sort | Dipranjan Laha |
| collection | DOAJ |
| description | Abstract Background Adrenocortical cancer (ACC) is a rare and aggressive cancer with dismal 5-year survival due to a lack of effective treatments. We aimed to identify a new effective combination of drugs and investigated their synergistic efficacy in ACC preclinical models. Methods A quantitative high-throughput drug screening of 4,991 compounds was performed on two ACC cell lines, SW13 and NCI-H295R, based on antiproliferative effect and caspase-3/7 activity. The top candidate drugs were pairwise combined to identify the most potent combinations. The synergistic efficacy of the selected inhibitors was tested on tumorigenic phenotypes, such as cell proliferation, migration, invasion, spheroid formation, and clonogenicity, with appropriate mechanistic validation by cell cycle and apoptotic assays and protein expression of the involved molecules. We tested the efficacy of the drug combination in mice with luciferase-tagged human ACC xenografts. To study the mRNA expression of target molecules in ACC and their clinical correlations, we analyzed the Gene Expression Omnibus and The Cancer Genome Atlas. Results We chose the maternal embryonic leucine zipper kinase (MELK) inhibitor (OTS167) and cyclin-dependent kinase (CDK) inhibitor (RGB-286638) because of their potent synergy from the pairwise drug combination matrices derived from the top 30 single drugs. Multiple publicly available databases demonstrated overexpression of MELK, CDK1/2, and partnering cyclins mRNA in ACC, which were independently associated with mortality and other adverse clinical features. The drug combination demonstrated a synergistic antiproliferative effect on ACC cells. Compared to the single-agent treatment groups, the combination treatment increased G2/M arrest, caspase-dependent apoptosis, reduced cyclins A2, B1, B2, and E2 expression, and decreased cell migration and invasion with reduced vimentin. Moreover, the combination effectively decreased Foxhead Box M1, Axin2, glycogen synthase kinase 3-beta, and β-catenin. A reduction in p-stathmin from the combination treatment destabilized microtubule assembly by tubulin depolymerization. The drug combination treatment in mice with human ACC xenografts resulted in a significantly lower tumor burden than those treated with single-agents and vehicle control groups. Conclusions Our preclinical study revealed a novel synergistic combination of OTS167 and RGB-286638 in ACC that effectively targets multiple molecules associated with ACC aggressiveness. A phase Ib/II clinical trial in patients with advanced ACC is therefore warranted. |
| first_indexed | 2024-04-12T04:25:01Z |
| format | Article |
| id | doaj.art-dedbd92387774c66a2f1443d619c0eaa |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-12T04:25:01Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-dedbd92387774c66a2f1443d619c0eaa2022-12-22T03:48:06ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662022-09-0141111610.1186/s13046-022-02464-5Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancerDipranjan Laha0Robert R.C. Grant1Prachi Mishra2Myriem Boufraqech3Min Shen4Ya-Qin Zhang5Matthew D. Hall6Martha Quezado7Michelly Sampaio De Melo8Jaydira Del Rivero9Martha Zeiger10Naris Nilubol11Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of HealthSurgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of HealthSurgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDepartment of Molecular Biosciences, College of Natural Sciences, Institute for Cellular and Molecular Biology, University of Texas at AustinNational Center for Advancing Translational Sciences, National Institutes of HealthNational Center for Advancing Translational Sciences, National Institutes of HealthNational Center for Advancing Translational Sciences, National Institutes of HealthLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthLaboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of HealthDevelopmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of HealthSurgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of HealthSurgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of HealthAbstract Background Adrenocortical cancer (ACC) is a rare and aggressive cancer with dismal 5-year survival due to a lack of effective treatments. We aimed to identify a new effective combination of drugs and investigated their synergistic efficacy in ACC preclinical models. Methods A quantitative high-throughput drug screening of 4,991 compounds was performed on two ACC cell lines, SW13 and NCI-H295R, based on antiproliferative effect and caspase-3/7 activity. The top candidate drugs were pairwise combined to identify the most potent combinations. The synergistic efficacy of the selected inhibitors was tested on tumorigenic phenotypes, such as cell proliferation, migration, invasion, spheroid formation, and clonogenicity, with appropriate mechanistic validation by cell cycle and apoptotic assays and protein expression of the involved molecules. We tested the efficacy of the drug combination in mice with luciferase-tagged human ACC xenografts. To study the mRNA expression of target molecules in ACC and their clinical correlations, we analyzed the Gene Expression Omnibus and The Cancer Genome Atlas. Results We chose the maternal embryonic leucine zipper kinase (MELK) inhibitor (OTS167) and cyclin-dependent kinase (CDK) inhibitor (RGB-286638) because of their potent synergy from the pairwise drug combination matrices derived from the top 30 single drugs. Multiple publicly available databases demonstrated overexpression of MELK, CDK1/2, and partnering cyclins mRNA in ACC, which were independently associated with mortality and other adverse clinical features. The drug combination demonstrated a synergistic antiproliferative effect on ACC cells. Compared to the single-agent treatment groups, the combination treatment increased G2/M arrest, caspase-dependent apoptosis, reduced cyclins A2, B1, B2, and E2 expression, and decreased cell migration and invasion with reduced vimentin. Moreover, the combination effectively decreased Foxhead Box M1, Axin2, glycogen synthase kinase 3-beta, and β-catenin. A reduction in p-stathmin from the combination treatment destabilized microtubule assembly by tubulin depolymerization. The drug combination treatment in mice with human ACC xenografts resulted in a significantly lower tumor burden than those treated with single-agents and vehicle control groups. Conclusions Our preclinical study revealed a novel synergistic combination of OTS167 and RGB-286638 in ACC that effectively targets multiple molecules associated with ACC aggressiveness. A phase Ib/II clinical trial in patients with advanced ACC is therefore warranted.https://doi.org/10.1186/s13046-022-02464-5Adrenocortical cancerMaternal embryonic leucine zipper kinaseCyclin-dependent kinaseβ-cateninQuantitative high-throughput screeningTargeted therapy |
| spellingShingle | Dipranjan Laha Robert R.C. Grant Prachi Mishra Myriem Boufraqech Min Shen Ya-Qin Zhang Matthew D. Hall Martha Quezado Michelly Sampaio De Melo Jaydira Del Rivero Martha Zeiger Naris Nilubol Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer Journal of Experimental & Clinical Cancer Research Adrenocortical cancer Maternal embryonic leucine zipper kinase Cyclin-dependent kinase β-catenin Quantitative high-throughput screening Targeted therapy |
| title | Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer |
| title_full | Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer |
| title_fullStr | Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer |
| title_full_unstemmed | Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer |
| title_short | Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer |
| title_sort | preclinical assessment of synergistic efficacy of melk and cdk inhibitors in adrenocortical cancer |
| topic | Adrenocortical cancer Maternal embryonic leucine zipper kinase Cyclin-dependent kinase β-catenin Quantitative high-throughput screening Targeted therapy |
| url | https://doi.org/10.1186/s13046-022-02464-5 |
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