title: Phosphorous dysregulation induced by MEK small molecule inhibitors in the rat involves blockade of FGF-23 signaling in the kidney.
abstract: MEK, a kinase downstream of Ras and Raf oncogenes, constitutes a high priority target in oncology research. MEK small molecule inhibitors cause soft tissue mineralization in rats secondary to serum inorganic phosphorus (iP) elevation, but the molecular mechanism for this toxicity remains undetermined. We performed investigative studies with structurally distinct MEK inhibitors GEN-A and PD325901 (PD-901) in Sprague-Dawley rats. Our data support a mechanism that involves FGF-23 signal blockade in the rat kidney, causing transcriptional upregulation of 25-hydroxyvitamin D(3) 1-alpha-hydroxylase (Cyp27b1), the rate-limiting enzyme in vitamin D activation, and downregulation of 1,25-dihydroxyvitamin D(3) 24-hydroxylase (Cyp24a1), the enzyme that initiates the degradation of the active form of vitamin D. These transcriptional changes increase serum vitamin D levels, which in turn drive the increase in serum iP, leading to soft tissue mineralization in the rat.
authors: Safety Assessment, Genentech Inc., South San Francisco, California 94080, USA. dolores.diaz@gene.com
authors: Dolores
authors: D
authors: Diaz
authors: Krishna
authors: K
authors: Allamneni
authors: Jacqueline M
authors: JM
authors: Tarrant
authors: Sock-Cheng
authors: SC
authors: Lewin-Koh
authors: Rama
authors: R
authors: Pai
authors: Preeti
authors: P
authors: Dhawan
authors: Gary R
authors: GR
authors: Cain
authors: Cleopatra
authors: C
authors: Kozlowski
authors: Hajime
authors: H
authors: Hiraragi
authors: Nghi
authors: N
authors: La
authors: Dylan P
authors: DP
authors: Hartley
authors: Xiao
authors: X
authors: Ding
authors: Brian J
authors: BJ
authors: Dean
authors: Sheila
authors: S
authors: Bheddah
authors: Donna M
authors: DM
authors: Dambach
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006706:Homeostasis / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010281:Parathyroid Hormone / Q000097:blood; D010758:Phosphorus / Q000097:blood*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D053719:Tandem Mass Spectrometry; D014807:Vitamin D / Q000097:blood
chemical_list: D010281:Parathyroid Hormone; D047428:Protein Kinase Inhibitors; D014807:Vitamin D; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium