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.

癌症恶病质是一种常见的、使人衰弱的疾病，治疗选择有限。使用已建立的肺癌小鼠模型，我们发现恶病质的特征是食物摄入量、自发活动和能量消耗减少，并伴有肌肉代谢功能障碍和萎缩。我们确定激活素 A 据称是恶病质的驱动因素，并用 ActRIIB-Fc（TGF-β/激活素家族成员的诱饵配体）与阿拉莫林 (Ana)（一种生长素释放肽受体激动剂）一起治疗，分别逆转肌肉功能障碍和厌食症。安娜有效地增加了食物摄入量，但只有药物组合才能增加瘦体重、恢复自发活动并提高总体生存率。这些有益作用仅限于雌性小鼠，并且取决于卵巢功能。一致认为，人类肺腺癌中激活素 A 的高表达仅与女性患者的不良预后相关，尽管两性的表达水平相似。这项研究表明，需要多模式、针对性别的疗法来逆转恶病质。