Bates DO

Breininger SP

Clarke PA

Collier P

Cowie A

Garbis SD

Gibson J

Grabowska AM

Harrington J

Hayden A

Izadi F

Jaynes E

Kyle E

Manousopoulou A

Mongan NP

Parsons SL

Pickering O

Ritchie AA

Rose-Zerilli M

Saunders JH

Sharpe BP

Underwood TJ

Walker RC

Walters Z

Yacqub-Usman K

English

\ua9 2022 The AuthorsThe chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction

Newcastle University E-Prints

Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts

https://eprints.ncl.ac.uk/file_store/production/294532/384E53C0-7D9B-4EAA-8065-369B7F9D1A82.pdf

Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts

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