Background and Purpose Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited treatment options. RYK, an atypical receptor‐like tyrosine kinase, has emerged as a potential regulator of tumour signalling, but its role in PDAC remains poorly understood. This study aimed to evaluate the anticancer potential of BJ‐2412, a novel sunitinib analogue with RYK‐inhibitory activity, and to elucidate the functional relevance of RYK in PDAC. Experimental Approach BJ‐2412 was synthesized by introducing a 2,4‐dimethylpyridin‐3‐ol moiety into sunitinib. Its anticancer activity was assessed in PDAC cell lines and mouse tumour models. Mechanistic studies included RTK phosphorylation profiling, RYK knockdown via siRNA, co‐immunoprecipitation, immunoblotting of downstream effectors, and analyses of apoptosis, invasion, and macrophage phenotypes. Key Results BJ‐2412 inhibited RYK phosphorylation by disrupting its interaction with EGFR. While RYK knockdown and BJ‐2412 had minimal effects on proliferation, both impaired cancer cell survival, including that of cancer stem cells. We identified RYK as a GSK‐3β activator that antagonizes canonical WNT signalling and RTK‐mediated GSK‐3β inhibition. BJ‐2412 inactivated GSK‐3β and reduced Sonic Hedgehog (Shh) and GLI1 expression. BJ‐2412‐induced up‐regulation of WNT5A, cancer cell‐selective apoptosis, M1‐macrophage polarization, as well as down‐regulation of MMPs and CTSS, were reversed by recombinant Shh. Finally, BJ‐2412 suppressed tumour growth, invasion, and metastasis in xenograft and allograft mouse models. Conclusions and Implications These findings identify RYK as a GSK‐3β activator and a therapeutic vulnerability in PDAC. BJ‐2412 demonstrates therapeutic potential by targeting this pathway and remodelling the tumour microenvironment, offering a multifaceted strategy against PDAC progression and resistance.
Yadav et al. (Thu,) studied this question.