Fig. 6: Combination of TKD and cetuximab in treating KRAS-mutant CRC PDX mouse models.

a KRAS G12D and G12V mutant tumor tissues derived from CRC patients were transplanted subcutaneously into NSG mice, and the mice received 7 times administration of PBS + Vehicle, cetuximab (200 μg/mouse) + vehicle, PBS + TKD (50 mg/kg), and cetuximab (200 μg/mouse) + TKD (50 mg/kg). n = 5. b CRC tumor weight statistic. n = 5. c The combination effect of cetuximab and TKD was analyzed by CI statistics. CI < 1 indicates synergistic effect. d Analysis of Ki-67-positive cells using IHC in CRC tumors. n = 3. Scale bar = 50 μm. e TKD degrades KRAS and sensitizes KRAS-mutant cancers to PD-1 antibody and cetuximab. TKD recognizes and enters cancer cells through BR2 peptide, and binds to KRAS by nanobody, then the TKD–KRAS complex is recognized and degraded by lysosomes via CTM motif. The KRAS degradation induced by TKD reverses the resistance of KRAS-mutant cancers to immunotherapy and targeted therapy. Statistical analyses were performed using ordinary one-way ANOVA except for b, in which Kruskal–Wallis test was performed; Error bars, SD; n.s. not significant; *P < 0.05; ****P < 0.0001.