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

Andre Lima Queiroz, Ezequiel Dantas, Shakti Ramsamooj, Anirudh Murthy, Mujmmail Ahmed, Elizabeth R. M. Zunica, Roger J. Liang, Jessica Murphy, Corey D. Holman, Curtis J. Bare, Gregory Ghahramani, Zhidan Wu, David E. Cohen, John P. Kirwan, Lewis C. Cantley, Christopher L. Axelrod and Marcus D. Goncalves ()
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Andre Lima Queiroz: Weill Cornell Medicine
Ezequiel Dantas: Weill Cornell Medicine
Shakti Ramsamooj: Weill Cornell Medicine
Anirudh Murthy: Weill Cornell Medicine
Mujmmail Ahmed: Weill Cornell Medicine
Elizabeth R. M. Zunica: Pennington Biomedical Research Center
Roger J. Liang: Weill Cornell Medicine
Jessica Murphy: Weill Cornell Medicine
Corey D. Holman: Weill Cornell Medicine
Curtis J. Bare: Weill Cornell Medicine
Gregory Ghahramani: Weill Cornell Medicine
Zhidan Wu: Pfizer Global R&D
David E. Cohen: Weill Cornell Medicine
John P. Kirwan: Pennington Biomedical Research Center
Lewis C. Cantley: Weill Cornell Medicine
Christopher L. Axelrod: Pennington Biomedical Research Center
Marcus D. Goncalves: Weill Cornell Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32135-0

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