Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients

Abstract

Background:Nintedanib is a clinically approved multikinase receptor inhibitor to treat non-small cell lung cancer with adenocarcinoma (ADC) histology in combination with docetaxel, based on the clinical benefits reported on ADC but not on squamous cell carcinoma (SCC), which are the two most common histologic lung cancer subtypes.Methods:We examined the potential role of tumour-associated fibroblasts (TAFs) in the differential effects of nintedanib in ADC and SCC. Because TAFs are largely quiescent and activated in histologic sections, we focused on the antifibrotic effects of nintedanib on TAFs stimulated with the potent fibroblast activator TGF-β1, which is upregulated in lung cancer.Results:Nintedanib dose-dependently inhibited the TGF-β1-induced expression of a panel of pro-fibrotic activation markers in both ADC-TAFs and control fibroblasts derived from uninvolved lung parenchyma, whereas such inhibition was very modest in SCC-TAFs. Remarkably, nintedanib abrogated the stimulation of growth and invasion in a panel of carcinoma cell lines induced by secreted factors from activated TAFs in ADC but not SCC, thereby supporting that TGF-β signalling and aberrant TAF–carcinoma cross-talk is regulated by different mechanisms in ADC and SCC.Conclusions:These results reveal that nintedanib is an effective inhibitor of fibrosis and its associated tumour-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that preclinical models based on carcinoma–TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumours.

Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer

“…Stromal TAFs have been implicated in virtually all steps of tumor progression [7]. Therefore it is unsurprising that stromal proteins, including those related to TAFs, are receiving increasing interest as biomarkers or therapeutic targets [9,30]. However, the prognostic value of standard markers of activated TAFs had remained ill defined in NSCLC.…”

“…This desmoplastic stroma is rich in activated fibroblasts (referred to as cancer-or tumorassociated fibroblasts (TAFs)), infiltrated immune cells and other less frequent cell types, in the background of an abundant deposition of fibrillar collagens and other fibrotic extracellular matrix components [4,5]. Of note, TAFs are largely responsible for the aberrant stromal deposition of fibrillar collagens within the tumor stroma [6], and are receiving increasing interest as a therapeutic target [7], as illustrated by the recent approval of the antiangiogenic and antifibrotic drug nintedanib to treat lung ADC patients in combination with docetaxel [8,9].…”

Conophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts

“…Antifibrotic drugs are thought to be candidates for targeting CAF because of their ability to suppress fibroblast activity. Actually, recent studies have shown that pirfenidone and the multi‐kinase inhibitor, nintedanib, which are drugs to treat idiopathic pulmonary fibrosis, can inhibit cancer progression through suppression of CAF in pancreatic cancer, breast cancer, and lung adenocarcinoma . It was reported that pirfenidone and nintedanib suppressed TGF‐β signaling and production of extracellular matrix components in tumor‐stromal interactions.…”

Novel Pyrimidines as Multitarget Protein Tyrosine Kinase Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

“…Pirfenidone ( 1 , Esbriet®) and nintedanib ( 2 , Ofev®) are the only two drugs that have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of IPF. Pirfenidone works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II, while nintedanib, is a well‐known multiprotein tyrosine kinase (PTK) inhibitor, which can inhibit the enzymatic activity of VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, PDGFα, and PDGFβ . GLPG1690 ( 3 ), a recently discovered autotaxin inhibitor, showed great efficacy in a bleomycin(BLM)‐induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung.…”

“…Pirfenidone works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II, [7,8] while nintedanib, is a wellknown multiprotein tyrosine kinase (PTK) inhibitor, which can inhibit the enzymatic activity of VEGFR1, VEGFR2, VEGFR3, FGFR1, FGFR2, FGFR3, PDGFα, and PDGFβ. [9][10][11] GLPG1690 (3), [12] a recently discovered autotaxin inhibitor, showed great efficacy in a bleomycin(BLM)-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung. GLPG1690 is now currently being evaluated in an exploratory phase III study in idiopathic pulmonary fibrosis patients (ClinicalTrials.gov Identifier: NCT03733444) ( Figure 1).…”