Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer

Publication Type Academic Article
Authors Queiroz AL, Dantas E, Ramsamooj S, Murthy A, Ahmed M, Zunica ERM, Liang RJ, Murphy J, Holman CD, Bare CJ, Ghahramani G, Wu Z, Cohen DE, Kirwan JP, Cantley LC, Axelrod CL, Goncalves MD
Journal Nature Communications
Volume 13
Date Published 08/08/2022

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.

DOI 10.1038/s41467-022-32135-0
PubMed ID 35941104
PubMed Central ID PMC9360437