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

ABSTRACT: Cancer cachexia is a common, debilitating condition with limited therapeutic options. The defining feature of cachexia is weight loss, which suggests a state of negative energy balance. Using an established genetically engineered mouse model of lung cancer, we found that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. Calorie restriction in wild-type mice does not recapitulate this phenotype, suggesting that reduced food intake is not the only driver of weight loss in this model. Using unbiased RNA-sequencing of the muscle and tumor, we identified Activin A as a purported driver of the peripheral metabolic dysfunction. To reverse anorexia and muscle dysfunction, we treated the mice with anamorelin (Ana), a ghrelin receptor agonist, alone or in combination with the ActRIIB-Fc, a decoy ligand for TGF-β/activin family members. Ana effectively increased food intake but only the combination of drugs increased lean mass, restored spontaneous activity, and improved overall survival. These beneficial effects were limited to female mice and were dependent on ovarian function. In agreement, we found that high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, even though expression levels are similar in both sexes. Overall, our study suggests that multimodal, sex-specific, therapies are needed to reverse CACS.

ORGANISM(S): Mus musculus

PROVIDER: GSE165856 | GEO | 2022/07/09

REPOSITORIES: GEO