Vitamin D3 Metabolites Demonstrate Prognostic Value in <i>EGFR</i>-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2020-03-01
• Series: Cancers
• Subjects: lung cancer; egfr; tyrosine kinase inhibitor; vitamin d; epithelial–mesenchymal transition
• Online Access: https://www.mdpi.com/2072-6694/12/3/675

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&#8722;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.