Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer‐associated fibroblast

Abstract

Cancer‐associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non–small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR‐mutant NSCLC cell lines, two KRAS‐mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial‐mesenchymal transition (EMT), and acquisition of resistance to molecular‐targeted therapy, including EGFR‐mutant NSCLC cells to osimertinib and of KRAS‐mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL‐6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF‐induced phospho‐STAT3 upregulation. Tranilast also inhibited CAF‐induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular‐targeted therapy reversed the CAF‐mediated resistance of the NSCLC cells to the molecular‐targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular‐targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer‐CAF interaction.

PDE5 inhibitors against cancer via mediating immune cells in tumor microenvironment: AI‐based approach for future drug repurposing exploration

“…CAFs‐targeted therapy for cancer is a potential anti‐tumor treatment. TME‐based screening for repurposes drugs targeting CAFs has been reported before, such as bortezomib, panobinostat, trinilast, midostaurin, anti‐IL‐6 receptor antibody, and PDE5 inhibitors 96–101 . Here, we investigated the functions of PDE5 inhibitors for mediating fibroblasts in TME (Table 4) 91 , 92 , 93 …”

“…TME-based screening for repurposes drugs targeting CAFs has been reported before, such as bortezomib, panobinostat, trinilast, midostaurin, anti-IL-6 receptor antibody, and PDE5 inhibitors. [96][97][98][99][100][101] Here, we investigated the functions of PDE5 inhibitors for mediating fibroblasts in TME (Table 4) 91,92,93 In this section, we paid attention to the association between PDE5 inhibitors and CAFs. Vardenafil targets PDE5 expressed in CAFs to suppress tumor invasion, and further enhances the efficacy of chemotherapy in preclinical models of esophageal adenocarcinoma.…”

Improving the Efficacy of Common Cancer Treatments via Targeted Therapeutics towards the Tumour and Its Microenvironment

“…Tranilast (N-(3,4-Dimethoxycinnamoyl)anthranilic acid) is an anti-fibrotic drug that has been used in combination with doxorubicin—a clinically relevant chemotherapeutic drug—to reduce the stiffness of the stromal matrix [ 129 ]. It has also shown potential to target CAFs by inhibiting cross-talk with non-small-cell lung cancer cells [ 161 ]. A current Phase I/II clinical trial (NCT05626829) is recruiting to evaluate the effectiveness of Tranilast as a radiosensitizer for nasopharyngeal carcinoma, with completion aimed at Fall 2024.…”

Ferroptosis and EMT: key targets for combating cancer progression and therapy resistance

“…These findings provide a therapeutic alternative for osimertinib-resistant NSCLC cells that undergo EMT. Treatment strategies for NSCLC cells that are resistant to osimertinib include inhibiting the NF-kB pathway or focusing on GPX4 to stop EMT [ 78 ].…”