Pharmacological inhibition of IRAK4 kinase activity does not prevent cachexia in mice with pancreatic cancer

Abstract

Background

Inflammation is a hallmark of cachexia; however, effective anti-inflammatory treatments have not yet been identified. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key signalling node linking interleukin-1 receptor (IL-1R) and toll-like receptor (TLR) activation to the production of multiple proinflammatory cytokines that are elevated in cancer cachexia. The purpose of this work is to evaluate whether pharmacological inhibition of IRAK4 kinase activity with PF-06426779 could prevent cachexia using a model of pancreatic cancer. The effect of appetite stimulation via the ghrelin receptor agonist anamorelin was also examined as a benchmark of clinically validated mechanisms.

Methods

Female C57Bl/6J mice were given an intraperitoneal injection of Kras^G12D; p53^R172H; Pdx1-Cre (KPC) pancreatic tumour cells. PF-06426779 or anamorelin treatment was initiated at the onset of anorexia. Body weight and food intake were measured throughout the study. Body composition, muscle function (force), and physical activity (treadmill running endurance) were assessed at the end of the study.

Results

Chronic treatment with PF-06426779, at doses covering in vitro IC50 and IC90 at C_min, did not increase body weight, food intake, and muscle function in the KPC tumour model. In contrast, anamorelin (vs. vehicle) increased food intake (P < 0.01), hindlimb skeletal muscle mass (P < 0.01), and muscle strength (P < 0.05); however, treadmill running endurance was not increased.

Conclusions

These data suggest that inhibition of IRAK4 kinase activity is not sufficient to treat cachexia, at least in pancreatic cancer, and exploration of alternative anti-inflammatory strategies that increase appetite is required.