A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Jessica L. Chitty, Michelle Yam, Lara Perryman, Amelia L. Parker, Joanna N. Skhinas, Yordanos F. I. Setargew, Ellie T. Y. Mok, Emmi Tran, Rhiannon D. Grant, Sharissa L. Latham, Brooke A. Pereira, Shona C. Ritchie, Kendelle J. Murphy, Michael Trpceski, Alison D. Findlay, Pauline Melenec, Elysse C. Filipe, Audrey Nadalini, Sipiththa Velayuthar, Gretel MajorKaitlin Wyllie, Michael Papanicolaou, Shivanjali Ratnaseelan, Phoebe Phillips, George Sharbeen, Janet Youkhana, Alice Russo, Antonia Blackwell, Jordan F. Hastings, Morghan C. Lucas, Cecilia R. Chambers, Daniel A. Reed, Janett Stoehr, Claire Vennin, Ruth Pidsley, Anaiis Zaratzian, Andrew M. Da Silva, Michael Tayao, Brett Charlton, David Herrmann, Max Nobis, Susan J. Clark, Andrew V. Biankin, Amber L. Johns, David R. Croucher, Adnan Nagrial, Anthony J. Gill, Sean M. Grimmond, Australian Pancreatic Cancer Genome Initiative (APGI), Australian Pancreatic Cancer Matrix Atlas (APMA), Marina Pajic, Paul Timpson, Wolfgang Jarolimek*, Thomas R. Cox*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)
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Abstract

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor 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 tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft 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 a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.
Original languageEnglish
Pages (from-to)1326-1344
Number of pages32
JournalNature Cancer
Volume4
Issue number9
Early online date28 Aug 2023
DOIs
Publication statusPublished - Sept 2023
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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