Selpercatinib mitigates cancer cachexia independent of anti-tumor activity in the HT1080 tumor model

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.