Breakthrough! RET Inhibitor Selpercatinib: The “Invisible Warrior” Against Cancer Cachexia

Recently, Cancer Letters published a groundbreaking study showing the impressive potential of the first highly selective RET inhibitor, Selpercatinib (LOXO-292), in the treatment of cancer cachexia. Experiments demonstrate that this drug significantly improves muscle atrophy, appetite loss, and metabolic disorders in tumor model mice, with its efficacy unrelated to tumor suppression. This discovery paves the way for new targeted therapies for cancer cachexia!

RET (Rearranged during Transfection) is a receptor tyrosine kinase belonging to the glial cell-derived neurotrophic factor (GDNF) receptor family. It activates downstream signaling pathways by binding to ligands such as GDNF and GDF15, regulating cell proliferation, differentiation, and survival. The RET signaling pathway plays a central role in neurodevelopment and kidney formation. Oncogenic RET fusions or mutations are most commonly found in non-small cell lung cancer (NSCLC) and thyroid cancer. Although their incidence in other cancers is lower, it is on the rise.

Currently, three RET inhibitors are available globally: Selpercatinib (LOXO-292), Pralsetinib (BLU-667), and Cabozantinib, all primarily indicated for cancer treatment. Despite high overall response rates (ORRs) with Selpercatinib and Pralsetinib, the proportion of patients achieving complete remission (CR) is under 10%. After RET TKI treatment, residual tumors inevitably develop resistance, caused by secondary target gene mutations, acquired alternative oncogenes, and MET amplification. The RET G810 mutation, located at the kinase solvent front, has been identified as the main mechanism of acquired resistance to Selpercatinib and Pralsetinib. Several next-generation RET TKIs that target these resistant RET mutations are currently in clinical trials. However, with the introduction of these new drugs, new RET mutations that adapt to TKIs are likely to emerge, leading to resistance against these next-generation RET TKIs. Solving this problem requires a deeper understanding of the multiple mechanisms that maintain RET TKI-resistant cells, identifying vulnerable targets, and designing effective combination therapies to eliminate residual tumors.

Abnormal activation of the GDF15-RET axis can trigger cachexia. GDF15 activates medullary neurons via RET, triggering anorexia; promoting lipolysis and muscle protein degradation, leading to rapid weight loss; and reducing thermogenesis, exacerbating body depletion. A new clinical finding shows that weight gain in RET-mutant cancer patients after treatment is unrelated to tumor relief, suggesting an independent mechanism of action. In animal models, after Selpercatinib treatment, HT1080 tumor-bearing mice showed a 30% increase in food intake, a 25% increase in skeletal muscle mass, and restored fat tissue to normal levels.

Kyinno Biotechnology, Inc. has developed multiple cell lines expressing common RET mutations associated with drug resistance, as well as in vivo animal models for in vitro and in vivo screening of BTK inhibitors. This supports the development of next-generation RET inhibitors, aiming to provide more effective and better-tolerated treatment options for cancer patients with RET mutations. Additionally, Kyinno Biotechnology, Inc. has established GDF15-induced in vivo models and various tumor cachexia models for validation. Selpercatinib has proven for the first time that RET-targeted therapy can independently improve cachexia, challenging the traditional belief that cancer treatment must focus solely on tumor suppression. This breakthrough may lead to the development of “dual-effect therapies” that both inhibit tumor growth and reverse body depletion, offering dual survival quality support for advanced patients. Some of the in vitro and in vivo validation results are as follows: