Khatri Ujjwol, Gouda Mohamed A, Pandey Shriya, Chauhan Neeraj K, Shen Tao, Hu Xueqing, Li Min, Huang Suming, Subbiah Vivek, Wu Jie
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cancer Lett. 2025 Jan 6;611:217444. doi: 10.1016/j.canlet.2025.217444.
Anorexia is a major cause of cancer cachexia and is induced by growth differentiation factor-15 (GDF15), which activates the rearranged during transfection (RET) protein tyrosine kinase in the hindbrain through GDF family receptor α-like (GFRAL), raising the possibility of targeting RET for cancer cachexia treatment. RET-altered cancer patients treated with RET-selective kinase inhibitors gain weight, however, it is unclear whether this results from tumor regression that improves the overall health of patients. Thus, the potential of using a RET inhibitor to address cancer cachexia remains unknown. Using a RET-negative tumor model, we evaluated the activity of the RET-selective inhibitor selpercatinib (LOXO-292) against cancer cachexia. In tumor-bearing animals, selpercatinib significantly increased food consumption, skeletal muscle mass and strength, adipose tissues, and body temperature, as well as reducing body weight loss, without significantly affecting tumor growth. Transcriptomes of skeletal muscle from mock-treated tumor-bearing mice were enriched in starvation and muscle atrophy genes, whereas those from selpercatinib-treated mice were enriched in myoblast proliferation, gluconeogenesis, and insulin receptor signaling genes. In parallel, retrospective analysis of weight gain in selpercatinib-treated patients showed that weight gain was not correlated with tumor response to selpercatinib. Our data demonstrate that selpercatinib could alleviate anorexia and cancer cachexia in an animal model and that weight gain in selpercatinib-treated patients is not dependent on tumor regression. These results identify a RET inhibitor as the first protein tyrosine kinase inhibitor for mitigating cancer cachexia.
厌食是癌症恶病质的主要原因，由生长分化因子15（GDF15）诱导，GDF15通过GDF家族受体α样蛋白（GFRAL）激活后脑中转染期间重排（RET）蛋白酪氨酸激酶，这增加了靶向RET治疗癌症恶病质的可能性。接受RET选择性激酶抑制剂治疗的RET改变的癌症患者体重增加，然而，尚不清楚这是否源于肿瘤消退从而改善了患者的整体健康状况。因此，使用RET抑制剂治疗癌症恶病质的潜力仍然未知。我们使用RET阴性肿瘤模型评估了RET选择性抑制剂塞尔帕替尼（LOXO-292）对癌症恶病质的活性。在荷瘤动物中，塞尔帕替尼显著增加了食物摄入量、骨骼肌质量和力量、脂肪组织以及体温，同时减少了体重减轻，而对肿瘤生长没有显著影响。未处理的荷瘤小鼠骨骼肌的转录组富含饥饿和肌肉萎缩基因，而塞尔帕替尼处理的小鼠的转录组则富含成肌细胞增殖、糖异生和胰岛素受体信号基因。同时，对接受塞尔帕替尼治疗患者体重增加的回顾性分析表明，体重增加与肿瘤对塞尔帕替尼的反应无关。我们的数据表明，塞尔帕替尼可以在动物模型中减轻厌食和癌症恶病质，并且接受塞尔帕替尼治疗患者的体重增加不依赖于肿瘤消退。这些结果确定RET抑制剂是第一种用于减轻癌症恶病质的蛋白酪氨酸激酶抑制剂。
