Pentoxifylline and pirfenidone sensitize pancreatic cancer cells to gemcitabine treatment

Abstract

Repurposing “old” drugs is an attractive strategy for cancer drug discovery, particularly for cancers with limited chemotherapeutic options and/or high therapy resistance, such as pancreatic ductal adenocarcinoma (PDAC). Drug resistance in PDAC is highly influenced by the tumor microenvironment, especially by macrophages. Extracellular vesicles (EVs) released by macrophages might have a role in PDAC drug resistance, by carrying cargo from their donor macrophages. Therefore, we aimed to i) identify, in the cargo of EVs shed by macrophages, proteins responsible for decreasing sensitivity to gemcitabine (standard-based chemotherapy in PDAC) and ii) study in PDAC cells the antitumor effect of drugs clinically approved for other diseases and known to inhibit those protein targets as an off-target effect. Proteomic analysis identified Fibronectin (FN1) and Chitinase 3-like 1 (CH3IL1) as abundantly present in EVs cargo released by human macrophages. Recombinant human proteins, rhCHI3L1 and rhFN, reduced PDAC cellular sensitivity to gemcitabine through the ERK pathway. Immunohistochemistry of PDAC tumor patient samples showed that expression of FN1 and CH3IL1 was associated to high presence of macrophages. The Cancer Genome Atlas confirmed an association of CHI3L1 and FN1 gene expression with PDAC patients overall survival, gemcitabine response and macrophage infiltration. Inhibition of CHI3L1 by pentoxifylline (approved drug for peripheral arterial disease) and of FN1 by pirfenidone (an antifibrotic drug for the treatment of idiopathic pulmonary fibrosis), partially reverted gemcitabine resistance induced by the respective recombinant proteins. Additional work will be performed in xenograft mice models of PDAC, to further study the possibility of repurposing pirfenidone and pentoxifylline for PDAC treatment.