A First-in-Class Pan-Lysyl Oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

The lysyl oxidase family represents a promising target in stromal targeting of solid tumours due to the importance of this family in cross-linking and stabilising fibrillar collagens, and its known role in tumour desmoplasia. Using small-molecule drug design approaches, we generated and validated PXS-5505, a first-in-class, highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumour desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumour perfusion, and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, whilst also demonstrating anti-fibrotic effects in human PDX models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of the first pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma. Transcriptome analysis of p53_educated cancer-associated fibroblasts (CAFs), isolated from the KPC (PDX1cre, KrasG12D/+,p53R172H/+,Ecad-GFP/+) mouse model of pancreatic ductal adenocarcinoma, assessed by RNASequencing.