期刊
CANCERS
卷 12, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/cancers12030675
关键词
lung cancer; EGFR; tyrosine kinase inhibitor; vitamin D; epithelial-mesenchymal transition
类别
资金
- Roswell Park Comprehensive Cancer Center National Cancer Institute [P30CA016056]
- Herd of Hope Award from the Roswell Park Alliance Foundation
- NIH [R03 CA249411, R01 DE024595]
EGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with EGFR-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 patientswith EGFR-mutant LUAD that received EGFR TKIs (erlotinib n = 20 and afatinib n = 1). Patientswhowere 25(OH)D3-sufficient experienced significantly longer benefit fromEGFR TKI therapy (mean 14.5 months) than those with 25(OH)D3 insufficiency (mean 10.6 months, p = 0.026). In contrast, 25(OH)D3 had no prognostic value in patients with KRAS-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-EMTmodel of resistance. We conclude that vitamin D sufficiency portends increased PFS among EGFR-mutant LUAD patients that receive EGFR TKIs, and that vitamin D signaling maintains drug efficacy in this specific patient subset by opposing EMT.
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