Mechanisms of soft-tissue mineralization induced by the inhibition of the MEK/ERK pathway or the inhibition of fibroblast growth factor receptors

Graça, Joao Alberto 2016. Mechanisms of soft-tissue mineralization induced by the inhibition of the MEK/ERK pathway or the inhibition of fibroblast growth factor receptors. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Currently in development as anti-cancer drugs, MEK/ERK and FGFR inhibitors have induced soft-tissue mineralization and increased plasma Pi and 1,25-dihydroxyvitamin D3 (1,25D3) levels in pre-clinical studies. AstraZeneca in-house data reported softtissue mineralization in stomach, kidney and heart of rats administered for >7d with MEK (MEKi) or FGFR (FGFRi) inhibitors. In this study, I aimed to unravel the mechanisms of soft-tissue mineralization associated with MEK/ERK or FGFR inhibition by assessing key processes for mineral homeostasis in rats treated with these inhibitors. The main findings of this study are: 1) Supporting previous studies, MEKi and FGFRi treatment (8d) resulted in softtissue mineralization and increases in plasma Pi and FGF23. Importantly, similar effects were observed for the first time in animals treated with an ERK inhibitor (ERKi). 2) Renal CaSR expression remained unchanged following MEKi or FGFRi treatment (8d), suggesting that the CaSR is not key for the mineralization induced by these inhibitors. Additionally, CaSR expression was detected throughout the nephron which supports previously hypothesised roles for this receptor in different processes including 1,25D3 production and Pi reabsorption. 3) Acute dosing (6h) with ERKi or FGFRi resulted in reduced plasma FGF23 and altered renal expression of proteins involved in 1,25D3 production (Cyp27b1, Cyp24a1) and Pi reabsorption (NaPiIIa), effects indicative of an impared FGF23 signalling. These results are consistent with MEK/ERK and FGFR inhibition promoting soft-tissue mineralization by analogous mechanisms: a blockage of FGF23 signalling that results in increased 1,25D3 production and in the consequent toxicity. 4) Repeated dosing (8d) with MEKi and FGFRi resulted in increased renal expression of Ca2+-transport (TRPV5, calbindin-D28k, PMCA) and of calcification-inducing (alkaline phosphatase) proteins. These increases may contribute to mineralization by locally raising Ca2+xPi product and inducing a pro-calcifying environment. Since the identified proteins contain VDREs, these effects are likely to be induced by increased plasma 1,25D3 levels.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > QR Microbiology
Uncontrolled Keywords:	Renal CaSR distribution; FGFR inhibitor; MEK inhibitor; Soft-tissue mineralization
Funders:	Marie Curie Fellowship
Date of First Compliant Deposit:	30 March 2016
Last Modified:	22 Dec 2021 11:50
URI:	https://orca.cardiff.ac.uk/id/eprint/85896

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