Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance
EGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with <i>EGFR</i>-mutant lung adenocarcinoma (LUAD). Although initially effective, EGFR TKIs are not curative. Disease inevitably relapses due to acquired drug resistance. We hypothesized that vita...
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| Format: | Article |
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/3/675 |
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| author | Tatiana Shaurova Grace K Dy Sebastiano Battaglia Alan Hutson Letian Zhang Yunkai Zhang Christine M Lovly Mukund Seshadri David W Goodrich Candace S Johnson Pamela A Hershberger |
| author_facet | Tatiana Shaurova Grace K Dy Sebastiano Battaglia Alan Hutson Letian Zhang Yunkai Zhang Christine M Lovly Mukund Seshadri David W Goodrich Candace S Johnson Pamela A Hershberger |
| author_sort | Tatiana Shaurova |
| collection | DOAJ |
| description | EGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with <i>EGFR</i>-mutant lung adenocarcinoma (LUAD). Although initially effective, EGFR TKIs are not curative. Disease inevitably relapses due to acquired drug resistance. We hypothesized that vitamin D metabolites could be used with EGFR TKIs to prevent therapeutic failure. To test this idea, we investigated the link between serum 25-hydroxyvitamin D3 (25(OH)D3) and progression-free survival (PFS) in patients with <i>EGFR</i>-mutant LUAD that received EGFR TKIs (erlotinib n = 20 and afatinib n = 1). Patients who were 25(OH)D3-sufficient experienced significantly longer benefit from EGFR TKI therapy (mean 14.5 months) than those with 25(OH)D3 insufficiency (mean 10.6 months, <i>p</i> = 0.026). In contrast, 25(OH)D3 had no prognostic value in patients with <i>KRAS</i>-mutant LUAD that received cytotoxic chemotherapy. To gain mechanistic insights, we tested 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity in vitro. 1,25(OH)2D3 promoted epithelial differentiation and restored EGFR TKI sensitivity in models of EGFR TKI resistance that were associated with epithelial−mesenchymal transition (EMT). 1,25(OH)2D3 was ineffective in a non-EMT model of resistance. We conclude that vitamin D sufficiency portends increased PFS among <i>EGFR</i>-mutant LUAD patients that receive EGFR TKIs, and that vitamin D signaling maintains drug efficacy in this specific patient subset by opposing EMT. |
| first_indexed | 2024-03-12T11:09:40Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T11:09:40Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-870863c871444f97a94b2e05754308d82023-09-02T03:04:53ZengMDPI AGCancers2072-66942020-03-0112367510.3390/cancers12030675cancers12030675Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic ResistanceTatiana Shaurova0Grace K Dy1Sebastiano Battaglia2Alan Hutson3Letian Zhang4Yunkai Zhang5Christine M Lovly6Mukund Seshadri7David W Goodrich8Candace S Johnson9Pamela A Hershberger10Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USACenter for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Medicine and Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Medicine and Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USADepartment of Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USADepartment of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USAEGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with <i>EGFR</i>-mutant lung adenocarcinoma (LUAD). Although initially effective, EGFR TKIs are not curative. Disease inevitably relapses due to acquired drug resistance. We hypothesized that vitamin D metabolites could be used with EGFR TKIs to prevent therapeutic failure. To test this idea, we investigated the link between serum 25-hydroxyvitamin D3 (25(OH)D3) and progression-free survival (PFS) in patients with <i>EGFR</i>-mutant LUAD that received EGFR TKIs (erlotinib n = 20 and afatinib n = 1). Patients who were 25(OH)D3-sufficient experienced significantly longer benefit from EGFR TKI therapy (mean 14.5 months) than those with 25(OH)D3 insufficiency (mean 10.6 months, <i>p</i> = 0.026). In contrast, 25(OH)D3 had no prognostic value in patients with <i>KRAS</i>-mutant LUAD that received cytotoxic chemotherapy. To gain mechanistic insights, we tested 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity in vitro. 1,25(OH)2D3 promoted epithelial differentiation and restored EGFR TKI sensitivity in models of EGFR TKI resistance that were associated with epithelial−mesenchymal transition (EMT). 1,25(OH)2D3 was ineffective in a non-EMT model of resistance. We conclude that vitamin D sufficiency portends increased PFS among <i>EGFR</i>-mutant LUAD patients that receive EGFR TKIs, and that vitamin D signaling maintains drug efficacy in this specific patient subset by opposing EMT.https://www.mdpi.com/2072-6694/12/3/675lung canceregfrtyrosine kinase inhibitorvitamin depithelial–mesenchymal transition |
| spellingShingle | Tatiana Shaurova Grace K Dy Sebastiano Battaglia Alan Hutson Letian Zhang Yunkai Zhang Christine M Lovly Mukund Seshadri David W Goodrich Candace S Johnson Pamela A Hershberger Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance Cancers lung cancer egfr tyrosine kinase inhibitor vitamin d epithelial–mesenchymal transition |
| title | Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance |
| title_full | Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance |
| title_fullStr | Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance |
| title_full_unstemmed | Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance |
| title_short | Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance |
| title_sort | vitamin d3 metabolites demonstrate prognostic value in i egfr i mutant lung adenocarcinoma and can be deployed to oppose acquired therapeutic resistance |
| topic | lung cancer egfr tyrosine kinase inhibitor vitamin d epithelial–mesenchymal transition |
| url | https://www.mdpi.com/2072-6694/12/3/675 |
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