The tyrosine-kinase inhibitor Nintedanib ameliorates autosomal-dominant polycystic kidney disease

Reena Rao,Darren P. Wallace,Sijo Mathew,Timothy A. Fields,Sreenath M. Suma,Abeda Jamadar,James P. Calvet

doi:10.1038/s41419-021-04248-9

Abstract

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and is characterized by progressive growth of fluid-filled cysts. Growth factors binding to receptor tyrosine kinases (RTKs) stimulate cell proliferation and cyst growth in PKD. Nintedanib, a triple RTK inhibitor, targets the vascular endothelial growth-factor receptor (VEGFR), platelet-derived growth-factor receptor (PDGFR), and fibroblast growth-factor receptor (FGFR), and is an approved drug for the treatment of non-small-cell lung carcinoma and idiopathic lung fibrosis. To determine if RTK inhibition using nintedanib can slow ADPKD progression, we tested its effect on human ADPKD renal cyst epithelial cells and myofibroblasts in vitro, and on Pkd1f/fPkhd1Cre and Pkd1RC/RC, orthologous mouse models of ADPKD. Nintedanib significantly inhibited cell proliferation and in vitro cyst growth of human ADPKD renal cyst epithelial cells, and cell viability and migration of human ADPKD renal myofibroblasts. Consistently, nintedanib treatment significantly reduced kidney-to-body-weight ratio, renal cystic index, cystic epithelial cell proliferation, and blood-urea nitrogen levels in both the Pkd1f/fPkhd1Cre and Pkd1RC/RC mice. There was a corresponding reduction in ERK, AKT, STAT3, and mTOR activity and expression of proproliferative factors, including Yes-associated protein (YAP), c-Myc, and Cyclin D1. Nintedanib treatment significantly reduced fibrosis in Pkd1RC/RC mice, but did not affect renal fibrosis in Pkd1f/fPkhd1Cre mice. Overall, these results suggest that nintedanib may be repurposed to effectively slow cyst growth in ADPKD.

Highlights

In PKD kidneys, cysts develop from the renal tubules and progressively enlarge due to cell proliferation and fluid secretion by tubular epithelial cells [1]
In this study, we show for the first time that nintedanib, an FDAapproved triple receptor tyrosine kinases (RTKs) inhibitor, significantly reduces Autosomal-dominant polycystic kidney disease (ADPKD) disease progression
We demonstrated that in vitro, nintedanib reduced human ADPKD renal cystic epithelial cell proliferation and cyst growth, as well as reduced ADPKD renal myofibroblast migration and cell viability

Summary

INTRODUCTION

In PKD kidneys, cysts develop from the renal tubules and progressively enlarge due to cell proliferation and fluid secretion by tubular epithelial cells [1]. Multiple small-molecule inhibitors of RTKs have been developed to target the ATP-binding site of the intracellular tyrosine kinase domain. FDA-approved small-molecule inhibitors and monoclonal antibodies that interfere with RTK activation are currently used for the treatment of cancer and lung disease [5, 6]. The main RTKs that were studied in PKD are EGFR, HER2, and VEGFR. Inhibition of EGFR and VEGFR was shown to slow cyst growth in various PKD rodent models [7,8,9,10,11,12,13]. Tesevatinib, an inhibitor of EGFR, HER2, c-SRC, and VEGFR, which reduced cyst growth in autosomalrecessive PKD (ARPKD) mice [10], was recently tested for efficacy and safety in a clinical phase-2 study in ADPKD patients (ClinicalTrials.gov Identifier: NCT03203642). Nintedanib has undergone extensive human trials [5, 15, 16] and is currently approved by the US FDA for therapy for idiopathic pulmonary fibrosis, interstitial lung disease associated with systemic sclerosis, and chronic

Jamadar et al 2

RESULTS

DISCUSSION

MATERIALS AND METHODS