Dual-modified antisense oligonucleotides targeting oncogenic protocadherin to treat gastric cancer

The objective of this study was to develop an innovative treatment strategy utilizing antisense oligonucleotides (ASOs) that target the gene encoding protocadherin alpha 11 (PCDHA11) and to elucidate the role of PCDHA11 in gastric cancer cells. We designed and screened 54 amido-bridged nucleic acid (AmNA)-modified ASOs, selecting them based on PCDHA11-knockdown efficacy, in vitro and in vivo activity, and off-target effects. We assessed the impact of AmNA-modified anti-PCDHA11 ASOs on cellular functions and signaling pathways, and investigated the effects of Pcdha11 deficiency in mice. AmNA-modified anti-PCDHA11 ASOs significantly reduced the proliferation of gastric cancer cells and other solid tumors, whereas overexpression of PCDHA11 enhanced cell proliferation. The selected ASOs inhibited cellular functions related to the metastatic potential of gastric cancer cells, including migration, invasiveness, spheroid formation, and cancer stemness. Our findings revealed that AmNA-modified anti-PCDHA11 ASOs disrupted the AKT/mTOR, Wnt/β-catenin, and JAK/STAT signaling pathways. In mouse models of peritoneal metastasis (gastric and pancreatic cancer), systemic metastasis, and established subcutaneous tumors, administration of AmNA-modified anti-PCDHA11 ASOs inhibited tumor growth. ASO treatment induced reversible, dose- and sequence-dependent liver damage. Pcdha11-deficient mice demonstrated normal reproductive, organ, and motor functions. AmNA-modified anti-PCDHA11 ASOs offer a promising therapeutic strategy for the treatment of gastric cancer and other solid malignancies.