Dual targeting of chemoresistance and ferroptosis in gastric cancer: DDR1/VEGFR2 inhibitor K-13 synergizes with docetaxel from preclinical models to phase Ib/II clinical trial.

Chemotherapy remains a cornerstone therapeutic approach for gastric cancer (GC). However, the clinical efficacy of docetaxel is substantially limited by the emergence of drug resistance. Here, we discovered a novel DDR1/VEGFR2 inhibitor, K-13, and further confirmed its selectivity by comprehensive kinase profiling in vitro. Through screening of K-13 in combination with conventional chemotherapeutic agents in GC, we identified a pronounced synergistic effect between K-13 and docetaxel. The combination therapy demonstrated significant antitumor effects in GC cell lines, human GC patient-derived organoids (PDOs), human GC acquired docetaxel-resistant PDOs, subcutaneous xenograft models, and patient-derived xenograft (PDX) models. Mechanistically, K-13 synergized with docetaxel to inhibit Ribonucleotide Reductase M2 (RRM2) to block the AKT/mTOR pathway to reverse resistance and induce ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde accumulation (MDA), and iron overload. These findings were consistently validated across all preclinical models. The translational potential of this strategy is currently being evaluated in an ongoing phase Ib/II clinical trial, and two partial responses (PRs) have already been observed in patients receiving the combination therapy. These findings underscore dual inhibition of DDR1 and VEGFR2 as a promising therapeutic approach to overcome docetaxel resistance in GC. Graphical abstract: Targeting the dual inhibition of DDR1 and VEGFR2 provides a promising therapeutic strategy to overcome docetaxel resistance in GC. The combination potently inhibited tumor growth across cell lines, PDOs, and PDX models by suppressing RRM2 and blocking AKT/mTOR signaling, ultimately inducing ferroptosis. The translational potential of this strategy is being evaluated in an ongoing phase Ib/II clinical trial, and two partial responses (PRs) have already been observed in patients receiving the combination therapy.