Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis
Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide clinical benefits over chemotherapy for lung cancer patients with EGFR activating mutations. Despite initial clinical responses, long‐term efficacy is not possible because of acquired resistance to these thera...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-02-01
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| Series: | FASEB BioAdvances |
| Subjects: | |
| Online Access: | https://doi.org/10.1096/fba.2019-00081 |
| _version_ | 1828426371439788032 |
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| author | Mark C. Howell Ryan Green Roukiah Khalil Elspeth Foran Waise Quarni Rajesh Nair Stanley Stevens Aleksandr Grinchuk Andrew Hanna Shyam Mohapatra Subhra Mohapatra |
| author_facet | Mark C. Howell Ryan Green Roukiah Khalil Elspeth Foran Waise Quarni Rajesh Nair Stanley Stevens Aleksandr Grinchuk Andrew Hanna Shyam Mohapatra Subhra Mohapatra |
| author_sort | Mark C. Howell |
| collection | DOAJ |
| description | Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide clinical benefits over chemotherapy for lung cancer patients with EGFR activating mutations. Despite initial clinical responses, long‐term efficacy is not possible because of acquired resistance to these therapies. We have developed EGFR TKI drug‐tolerant (DT) human lung cancer cell lines as a model for de novo resistance. Mass spectroscopic analysis revealed that the cytochrome P450 protein, CYP51A1 (Lanosterol 14α‐demethylase), which is directly involved with cholesterol synthesis, was significantly upregulated in the DT cells. Total cellular cholesterol, and more specifically, mitochondrial cholesterol, were found to be upregulated in DT cells. We then used the CYP51A1 inhibitor, ketoconazole, to downregulate cholesterol synthesis. In both parental and DT cells, ketoconazole and EGFR TKIs acted synergistically to induce apoptosis and overcome the development of EGFR tolerance. Lastly, this combination therapy was shown to shrink the growth of tumors in an in vivo mouse model of EGFR TKI resistance. Thus, our study demonstrates for the first time that ketoconazole treatment inhibits upregulation of mitochondrial cholesterol and thereby overcomes EGFR‐TKI resistance in lung cancer cells. |
| first_indexed | 2024-12-10T16:44:10Z |
| format | Article |
| id | doaj.art-4b4892bbe93d40b59fc606382cc4bdda |
| institution | Directory Open Access Journal |
| issn | 2573-9832 |
| language | English |
| last_indexed | 2024-12-10T16:44:10Z |
| publishDate | 2020-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | FASEB BioAdvances |
| spelling | doaj.art-4b4892bbe93d40b59fc606382cc4bdda2022-12-22T01:41:06ZengWileyFASEB BioAdvances2573-98322020-02-01229010510.1096/fba.2019-00081Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesisMark C. Howell0Ryan Green1Roukiah Khalil2Elspeth Foran3Waise Quarni4Rajesh Nair5Stanley Stevens6Aleksandr Grinchuk7Andrew Hanna8Shyam Mohapatra9Subhra Mohapatra10Molecular Medicine Department University of South Florida Tampa FL USAMolecular Medicine Department University of South Florida Tampa FL USAMolecular Medicine Department University of South Florida Tampa FL USAMolecular Medicine Department University of South Florida Tampa FL USAMolecular Medicine Department University of South Florida Tampa FL USATransgenex Nanobiotech Inc Tampa FL USACell Biology, Microbiology, and Molecular Biology College of Arts and Sciences University of South Florida Tampa FL USAMolecular Medicine Department University of South Florida Tampa FL USAMolecular Medicine Department University of South Florida Tampa FL USACenter for Research & Education in Nanobioengineering University of South Florida Tampa FL USAMolecular Medicine Department University of South Florida Tampa FL USAAbstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide clinical benefits over chemotherapy for lung cancer patients with EGFR activating mutations. Despite initial clinical responses, long‐term efficacy is not possible because of acquired resistance to these therapies. We have developed EGFR TKI drug‐tolerant (DT) human lung cancer cell lines as a model for de novo resistance. Mass spectroscopic analysis revealed that the cytochrome P450 protein, CYP51A1 (Lanosterol 14α‐demethylase), which is directly involved with cholesterol synthesis, was significantly upregulated in the DT cells. Total cellular cholesterol, and more specifically, mitochondrial cholesterol, were found to be upregulated in DT cells. We then used the CYP51A1 inhibitor, ketoconazole, to downregulate cholesterol synthesis. In both parental and DT cells, ketoconazole and EGFR TKIs acted synergistically to induce apoptosis and overcome the development of EGFR tolerance. Lastly, this combination therapy was shown to shrink the growth of tumors in an in vivo mouse model of EGFR TKI resistance. Thus, our study demonstrates for the first time that ketoconazole treatment inhibits upregulation of mitochondrial cholesterol and thereby overcomes EGFR‐TKI resistance in lung cancer cells.https://doi.org/10.1096/fba.2019-00081cholesteroldrug toleranceEGFR TKIslung cancer |
| spellingShingle | Mark C. Howell Ryan Green Roukiah Khalil Elspeth Foran Waise Quarni Rajesh Nair Stanley Stevens Aleksandr Grinchuk Andrew Hanna Shyam Mohapatra Subhra Mohapatra Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis FASEB BioAdvances cholesterol drug tolerance EGFR TKIs lung cancer |
| title | Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis |
| title_full | Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis |
| title_fullStr | Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis |
| title_full_unstemmed | Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis |
| title_short | Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis |
| title_sort | lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis |
| topic | cholesterol drug tolerance EGFR TKIs lung cancer |
| url | https://doi.org/10.1096/fba.2019-00081 |
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