Erlotinib Reduced Renal Inflammation in Alport Syndrome Mice, but Not Kidney Damage

Treatment with the drug erlotinib decreased kidney inflammation in mice with Alport syndrome, although it showed no impact in delaying disease progression.

Erlotinib, sold by Genentech under the brand name Tarceva, was approved by the U.S. Food and Drug Administration in 2004 to treat certain patients with non-small cell lung cancer.

The study, titled “Long-term treatment with EGFR inhibitor erlotinib attenuates renal inflammatory cytokines but not nephropathy in Alport syndrome mouse model,” was published in the journal Clinical and Experimental Nephrology.

The glomerular basement membrane (GBM) is a key structural component of the kidney and plays a crucial function in the kidney filtration of waste from the blood. In Alport syndrome, there is an increased risk for GBM collapse leading to chronic inflammation and renal fibrosis, as well as end-stage renal disease.

Previous studies using a mouse model for human Alport syndrome (AS) identified an increase in certain proteins called tyrosine kinase receptors, which accompanied the GBM disorder. Epidermal growth factor receptor (EGFR) is a key tyrosine kinase receptor. But researchers were uncertain whether EGFR signaling was relevant to AS progression.

Researchers investigated the involvement of EGFR in Alport syndrome and how the suppression of EGFR signaling by erlotinib would affect AS progression. Erlotinib is a drug that inhibits EGFR signaling and was previously shown to suppress glomerular disease progression in an experimental model for inflammation of the kidneys (nephritis).

They analyzed kidney tissues of a mouse model of X-linked Alport syndrome and detected that EGFR is increased in the kidneys of Alport mice when compared to wild-type (control) mice. This suggested that that EGFR was activated in the kidneys of AS mice.

Mice were treated with erlotinib to determine whether inhibiting EGFR in mice with Alport could have a therapeutic effect, either by improving the disease or delaying disease progression. Mice were given the drug orally once a day (10 mg/kg) for 18 weeks. Urine samples were collected every week and renal function parameters were analyzed.

“Quantification of the data revealed that the glomerular injury and renal fibrosis scores in AS mice were not improved by erlotinib long-term treatment,” researchers wrote.

However, even though erlotinib did not improve renal disease in AS mice, researchers observed that it suppressed renal inflammation in these mice. Also, long‑term erlotinib treatment did not induce serious side effects in Alport mice.

Overall, “the findings presented here indicated that although the effects of EGFR signaling have some contribution to AS nephritis, it may not be the main signaling pathway involved in AS renal dysfunction, and that other signal transduction pathways need to be investigated for more consequential roles,” researchers concluded.