Lung Cancer Cells Survive Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exposure through Upregulation of Cholesterol Synthesis

Authors

Mark C. Howell, University of South FloridaFollow
Ryan Green, University of South FloridaFollow
Roukiah Khalil, University of South Florida
Elspeth Foran, University of South Florida
Waise Quarni, University of South Florida
Rajesh Nair, Transgenex Nanobiotech Inc
Stanley Stevens, University of South FloridaFollow
Aleksandr Grinchuk, University of South Florida
Andrew Hanna, University of South Florida
Shyam Mohapatra, University of South FloridaFollow
Subhra Mohapatra, University of South FloridaFollow

Document Type

Article

Publication Date

2020

Keywords

cholesterol, drug tolerance, EGFR TKIs, lung cancer

Digital Object Identifier (DOI)

https://doi.org/10.1096/fba.2019-00081

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.

Rights Information

This work is licensed under a Creative Commons Attribution 4.0 License.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

Faseb BioAdvances, v. 2, issue 2, p. 90-105

Scholar Commons Citation

Howell, Mark C.; Green, Ryan; Khalil, Roukiah; Foran, Elspeth; Quarni, Waise; Nair, Rajesh; Stevens, Stanley; Grinchuk, Aleksandr; Hanna, Andrew; Mohapatra, Shyam; and Mohapatra, Subhra, "Lung Cancer Cells Survive Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exposure through Upregulation of Cholesterol Synthesis" (2020). Molecular Medicine Faculty Publications. 24.
https://digitalcommons.usf.edu/mme_facpub/24