Ferroptosis and Cuproptosis Emerge as Key Cancer Therapy Targets in New Studies
Studies highlight ferroptosis and cuproptosis in cancer therapy: a DDR1/VEGFR2 inhibitor reverses gastric cancer chemoresistance, GSH-responsive nanoparticles enhance HCC immunotherapy, and nutrient restriction boosts Sorafenib-induced ferroptosis.
Ferroptosis and the related cell-death pathway cuproptosis are emerging as key targets in cancer therapy, according to a set of new studies covering gastric cancer, hepatocellular carcinoma, and immune checkpoint treatment.
In gastric cancer, a novel DDR1/VEGFR2 inhibitor called K-13 was found to synergize with docetaxel, reversing chemoresistance and inducing ferroptosis. The combination demonstrated antitumor effects in cell lines, patient-derived organoids, docetaxel-resistant organoids, subcutaneous xenografts, and patient-derived xenograft models. Mechanistically, K-13 synergized with docetaxel to inhibit Ribonucleotide Reductase M2 (RRM2), block the AKT/mTOR pathway, and induce ferroptosis, evidenced by mitochondrial alterations, lipid reactive oxygen species, malondialdehyde accumulation, and iron overload. The strategy is being evaluated in an ongoing phase Ib/II clinical trial, where two partial responses have already been observed. Emerging clinical data from other cancers support the DDR1 inhibitor-chemotherapy combination, including an 84% disease control rate in pancreatic cancer and a 41% response rate in triple-negative breast cancer.
In hepatocellular carcinoma (HCC), researchers designed copper complex nanoparticles (NPCu) and nanoparticles carrying the PI3K-AKT-mTOR inhibitor Alpelisib (NPALP). NPCu triggers mitochondrial dysfunction and promotes aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT), while NPALP induces apoptosis by inhibiting the PI3K-AKT-mTOR pathway. In mouse models, the combination activated antitumor immunity and, when combined with an anti-PD-1 antibody, significantly inhibited tumor progression and enhanced tumor infiltration of CD8+ T cells while reducing suppressive M2 macrophages and regulatory T cells.
Another study in HCC found that nutrient restriction or intermittent fasting enhanced Sorafenib-induced cell death both in vivo and in vitro by elevating ROS and MDA levels, promoting lipid peroxidation, and increasing intracellular Fe2+ accumulation. Key ferroptosis-associated proteins, including NRF2, GPX4, and HO-1, were significantly down-regulated by the combination, and glutathione supplementation reversed this effect. The authors concluded that nutrient restriction potentiates Sorafenib-induced ferroptosis via the NRF2/HO-1/GPX4 pathway. More than 10 clinical trials are currently evaluating fasting-mimicking diets in combination with various anticancer drugs.
A separate study identifies TMEM87a as a mediator of ferroptosis resistance, establishing a mechanistic link to Golgi pH homeostasis and exploring its relevance to immune checkpoint therapy.