The Multifaceted Role of Growth Differentiation Factor 15 (GDF15): A Narrative Review from Cancer Cachexia to Target Therapy

Abstract

Background: Growth Differentiation Factor 15 (GDF15) has emerged as a key biomarker and therapeutic target in oncology, with roles extending beyond cancer cachexia. Elevated GDF15 levels correlate with poor prognosis across several solid tumors, including colorectal, gastric, pancreatic, breast, lung, prostate, and head and neck cancers. GDF15 modulates tumor progression through PI3K/AKT, MAPK/ERK, and SMAD2/3 signaling, thereby promoting epithelial-to-mesenchymal transition, metastasis, immune evasion, and chemoresistance via Nrf2 stabilization and oxidative stress regulation. Methods: We performed a narrative review of the literature focusing on the role of GDF15 in solid tumors, with a particular emphasis on head and neck cancers. Results: In head and neck squamous cell carcinoma (HNSCC), GDF15 overexpression is linked to aggressive phenotypes, radioresistance, poor response to induction chemotherapy, and failure of immune checkpoint inhibitors (ICIs). Similar associations are observed in colorectal, pancreatic, and prostate cancer, where GDF15 contributes to metastasis and therapy resistance. Targeting the GDF15-GFRAL axis appears therapeutically promising: the monoclonal antibody ponsegromab improved cachexia-related outcomes in the PROACC-1 trial, while visugromab combined with nivolumab enhanced immune response in ICI-refractory tumors. Conclusions: Further investigation is warranted to delineate the role of GDF15 across malignancies, refine patient selection, and evaluate combinatorial approaches with existing treatments.

Keywords: GDF15; GFRAL; cachexia; cancer biomarker; chemotherapy resistance; head and neck cancer.

Figure 1

The various implications in both pathological and physiological conditions of GDF15 [42,43,44,45,46,47]. GDF15 has different physiological concentration gradients within the body, with the highest levels in placental tissue, the lowest in the kidney, liver, colon, pancreas, stomach, gallbladder, breast, lung, and endometrium, and intermediate levels in prostate and bladder. By binding GFRAL and exerting its action on the appetite areas located at the area postrema and nucleus of the solitary tract, GDF15 causes a significant reduction in food intake and weight and an increase in energetic expenditure. For these reasons, GDF15 is a major cause of CC syndrome characterized by anorexia, bone loss, adipose tissue depletion, muscle atrophy, and anemia. This is demonstrated by many preclinical studies on cellular lines and xenograft models and, for a second time, by the identification of higher levels of GDF15 in anorexic patients in comparison to ones with regular food intake. STN: Solitary tract nucleus.

Figure 2

Molecular pathways regulated by GDF15-GFRAL interaction [42,43,44,45,46,47]. GDF15 expression is transcriptionally regulated by multiple stress-responsive and inflammatory mediators, including p53, EGR-1, CHOP, ATF4, interleukin-1β (IL-1β), TNF-α, angiotensin II, and TGF-β. Upon translation and maturation, GDF15 is secreted as a mature homodimer and binds to the GFRAL receptor in the area postrema and nucleus tractus solitarius of the brainstem. This interaction induces a conformational change in GFRAL that allows for the recruitment and dimerization of the co-receptor RET (rearranged during transfection). The activated GDF15–GFRAL–RET complex initiates downstream signaling cascades involving ERK, AKT, PLC, and STAT3. These signals contribute to anorexia through inhibition of NPY neurons and activation of POMC neurons, stimulate glucocorticoid release via HPA axis activation, and promote fat loss. GDF15 also induces muscle atrophy by activating pro-apoptotic and proteolytic pathways (e.g., BAX, Caspase-3, Atrogin-1) and enhances bone resorption through RANKL-mediated osteoclastogenesis. Moreover, GDF15-mediated hepcidin suppression is associated with anemia, likely due to impaired iron homeostasis and erythropoiesis.