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Abstract
The signaling pathways of growth factors, including platelet-derived growth factor, can be considered specific targets for overcoming the poor prognosis of idiopathic pulmonary fibrosis. Nintedanib, the recently approved multiple kinase inhibitor, has shown promising antifibrotic effects in patients with idiopathic pulmonary fibrosis; however, its efficacy is still limited, and in some cases, treatment discontinuation is necessary owing to toxicities such as gastrointestinal disorders. Therefore, more effective agents with less toxicity are still needed. TAS-115 is a novel multiple tyrosine kinase inhibitor that preferably targets platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor, and c-FMS in addition to other molecules. In this study, we evaluated the antifibrotic effect of TAS-115 on pulmonary fibrosis in vitro and in vivo. TAS-115 inhibited the phosphorylation of PDGFR on human lung fibroblast cell line MRC-5 cells and suppressed their platelet-derived growth factor–induced proliferation and migration. Furthermore, TAS-115 inhibited the phosphorylation of c-FMS, a receptor of macrophage colony-stimulating factor, in murine bone marrow–derived macrophages and decreased the production of CCL2, another key molecule for inducing pulmonary fibrosis, under the stimulation of macrophage colony-stimulating factor. Importantly, the inhibitory effects of TAS-115 on both PDGFR and c-FMS were 3- to 10-fold higher than those of nintedanib. In a mouse model of bleomycin-induced pulmonary fibrosis, TAS-115 significantly inhibited the development of pulmonary fibrosis and the collagen deposition in bleomycin-treated lungs. These data suggest that strong inhibition of PDGFR and c-FMS by TAS-115 may be a promising strategy for overcoming the intractable pathogenesis of pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a life-threatening and chronic progressive fibrotic lung disease (1). Its pathological findings are characterized by excessive accumulation of extracellular matrix (ECM) and irreversible destruction of lung architecture. Although its detailed etiology is unknown, lung epithelial damage and subsequent excessive production of ECM, including collagen fibers, are considered clues to help in understanding the disease behavior. Because these pathogeneses are regulated by a variety of growth factors, targeting those molecules is suggested to be a promising strategy for treating patients with pulmonary fibrosis.
We have previously shown that among the growth factors involved in the pathogenesis of pulmonary fibrosis, the platelet-derived growth factor receptor (PDGFR) axis plays a crucial role in lung fibrosis in mice by enhancing the proliferation and migration of fibroblasts and fibrocytes (2–5). We demonstrated that the multiple kinase inhibitor imatinib mesylate, a drug originally developed to treat chronic myeloid leukemia by targeting BCR-ABL, possessed an antifibrotic effect by suppressing platelet-derived growth factor (PDGF) signaling (4, 5). Although the results of the clinical trial assessing the antifibrotic effect of imatinib on IPF were negative (6), the significance of the blockade of growth factor signaling in pulmonary fibrosis was recently demonstrated by clinical trials using nintedanib, which also targets multiple kinases, including PDGFR (7). The results showed that nintedanib reduced the decline in the respiratory function compared with placebo treatment in patients with IPF. The difference between the results of imatinib and nintedanib trials may be partly explained by differences in their inhibitory activities against PDGFR phosphorylation. The inhibitory effect of nintedanib on PDGF signaling is approximately 10-fold stronger than that of imatinib (8). However, whether nintedanib improves the survival of patients with IPF remains unclear, suggesting that treatment with nintedanib is still insufficient to overcome the intractable pathogenesis of pulmonary fibrosis. Furthermore, nintedanib often causes toxicities, such as gastrointestinal disorders, that can result in treatment discontinuation. Therefore, further efforts are needed to develop more selective and effective agents with less toxicity that target growth factor signaling to improve the prognosis of patients with pulmonary fibrosis.
TAS-115 is an oral tyrosine kinase inhibitor that suppresses the phosphorylation of PDGFR, vascular endothelial growth factor receptor (VEGFR), c-FMS, and MET (9, 10). A previous study using murine tumor models showed that the phosphorylation of PDGFR was suppressed with TAS-115 at less than 10 nM, which was lower than the corresponding concentration of nintedanib (half-maximal inhibitory concentrations [IC50] of nintedanib for PDGFR-α and -β reported as 59 and 65 nM, respectively (9, 11), suggesting that TAS-115 might also be useful as an antifibrotic drug. Furthermore, in addition to the blockade of PDGFR, TAS-115 inhibits macrophage colony-stimulating factor (M-CSF) signaling by inhibiting the phosphorylation of c-FMS, a receptor of M-CSF. M-CSF was reported to be involved in lung fibrotic change in mouse models by the induction of CCL2 (12), which is a key chemoattractant for fibrocytes (13). These results suggest that TAS-115 may exert favorable effects on pulmonary fibrosis by targeting the M-CSF–CCL2 axis in addition to PDGFR.
Currently, the pharmacological activity and preferable potency of TAS-115 to inhibit PDGFR and c-FMS have been shown only in tumor models (9, 10). We therefore hypothesized that TAS-115 also effectively attenuates lung fibrosis by inhibiting the phosphorylation of PDGFR and c-FMS. To assess this hypothesis, we conducted in vitro and in vivo studies to evaluate the effect of TAS-115 on pulmonary fibrosis and assessed its usefulness compared with nintedanib.
The detailed methods are described in the data supplement.
Eight-week-old C57BL/6 male mice were purchased from Charles River Japan Inc. The mice were maintained in the animal facility of Tokushima University according to the guidelines of Tokushima University (4). All experimental protocols were approved by the animal research committee of Tokushima University. TAS-115 was provided by Taiho Pharmaceutical. Nintedanib and bleomycin (BLM) were purchased from ChemScene and Nippon Kayaku Co., respectively. Recombinant human cytokines, including PDGF-BB, M-CSF, and transforming growth factor-β (TGF-β), were purchased from R&D Systems. Antibodies for PDGFR-β, phosphor-PDGFR-α/β, c-FMS, and phospho-c-FMS were purchased from Cell Signaling Technology. Anti–collagen I antibody was purchased from Abcam. Anti-ACTA2 antibody was purchased from Sigma-Aldrich. Anti–actin-β was purchased from Santa Cruz Biotechnology. MRC-5 cells were purchased from DS Pharma Biomedical. Murine lung fibroblasts were isolated according to a method reported previously (14). Bone marrow–derived macrophages (BMDMs) were obtained from mice as previously described (12).
Enzyme inhibition studies were performed using a mobility shift assay.
Immunoblotting was performed to assess the expression of proteins and the phosphorylation of PDGFR (15). The Simple Western system (ProteinSimple) was used to determine the phosphorylation of c-FMS.
A [3H]thymidine deoxyribose (3H-TdR) incorporation assay was performed to assess the proliferation of the fibroblasts.
The migration of fibroblasts was evaluated using a Transwell cell migration assay.
Quantitative reverse transcriptase–polymerase chain reaction was performed as previously described (16). The sequences of primers are described in the data supplement.
Concentrations of CCL2 and M-CSF were examined with an ELISA kit (R&D Systems). The concentrations of the other cytokines were measured by Bio-Plex assay (Bio-Rad Laboratories).
The mice received a single transbronchial instillation of 3.0 mg/kg BLM on Day 0. TAS-115, nintedanib, or distilled water was administered daily by gavage from Day 0. The dosage of TAS-115 was 30 mg/kg or 100 mg/kg, determined on the basis of a previous study evaluating its antitumor effect in vivo (9).
BAL was performed with saline (1 ml) using a soft cannula. After the cell numbers in the BAL fluid (BALF) were counted, cells were stained with Diff-Quik for cell classification (2).
The hydroxyproline contents of the BLM-treated lungs were measured using a hydroxyproline colorimetric assay kit (BioVision).
Murine lungs were embedded in paraffin, and the sections were stained with hematoxylin and eosin stain and Azan-Mallory stain. The fibrotic changes were evaluated by the Ashcroft score (17).
The significance of differences was analyzed using one-way ANOVA followed by Tukey’s multiple-comparisons post hoc test. P values less than 0.05 were considered to be significant.
Enzyme inhibition studies were performed to determine the IC50 of TAS-115 on PDGFR-α, PDGFR-β, VEGFR1–2, c-FMS, and fibroblast growth factor receptors (FGFR)1–3. The evaluated values of IC50 are shown in Table 1. TAS-115 inhibited the phosphorylation of PDGFR-α, PDGFR-β, VEGFR1, VEGFR2, and c-FMS effectively. In contrast, the IC50 values of TAS-115 against FGFRs were relatively high.
We evaluated the effect of TAS-115 on the phosphorylation of PDGFR in human fibroblast MRC-5 cells (Figures 1A and 1B). TAS-115 inhibited the phosphorylation of PDGFR in a dose-dependent manner, and its inhibitory effect was observed at 3 nM, which was lower than that observed with nintedanib. We then examined whether TAS-115 affected fibroblasts’ biological responses to PDGF-BB treatment using a 3H-TdR incorporation assay and Transwell migration assay (Figures 1C and 1D). The 3H-TdR incorporation assay showed that TAS-115 inhibited the PDGF-BB–induced proliferation of MRC-5 cells in a dose-dependent manner (Figure 1C). In addition, the Transwell migration assay showed that TAS-115 suppressed the PDGF-BB–induced migration of MRC-5 cells in a dose-dependent manner (Figure 1D). Of note, TAS-115 suppressed the proliferation of MRC-5 cells at 3 nM and the migration of cells at 1 nM, although nintedanib failed to inhibit migration at the same concentration. Similar effects of TAS-115 on PDGFR phosphorylation, cell proliferation, and cell migration were observed in murine primary lung fibroblasts (see Figure E1 in the data supplement). These data indicated that TAS-115 inhibited the phosphorylation of PDGFR and suppressed the biological activities of fibroblasts more effectively than nintedanib.
Figure 1. TAS-115 inhibits the phosphorylation of platelet-derived growth factor receptor (PDGFR) on MRC-5 cells and suppresses PDGF-induced proliferation and migration. (A) Human lung fibroblast MRC-5 cells were incubated with PDGF-BB (100 ng/ml) with or without different concentrations (0–1,000 nM) of TAS-115 or nintedanib. The phosphorylation of PDGFR was analyzed by immunoblotting. (B) Relative intensities of the bands of phosphorylated PDGFR-α/β to PDGFR-β are shown. The intensities were determined using a National Institutes of Health imaging program (n = 3). (C) The proliferation of MRC-5 cells was measured by a [3H]thymidine deoxyribose (3H-TdR) incorporation assay (n = 4). MRC-5 cells were incubated with PDGF-BB (100 ng/ml) with or without different concentrations (0–100 nM) of TAS-115 or nintedanib. (D) The migration of MRC-5 cells was assessed by performing a Transwell migration assay (n = 3). Fibroblasts plated on the upper chamber with a pore size of 8 μm were stimulated with PDGF-BB (100 ng/ml) added to the lower chamber. The indicated concentrations of TAS-115 or nintedanib were added to the upper chamber to assess their effect on cell migration. After 24 hours, the number of fibroblasts that had migrated to the bottom surface of the filter was counted. *P < 0.05 versus groups treated with PDGF-BB without TAS-115 or nintedanib; **P < 0.005 versus groups treated with PDGF-BB without TAS-115 or nintedanib; ***P < 0.001 versus groups treated with PDGF-BB without TAS-115 or nintedanib.
[More] [Minimize]The production of ECM and ACTA2, which are strongly induced by TGF-β stimulation, is the hallmark of pulmonary fibrosis (13). We next explored if TAS-115 had an activity to suppress TGF-β–stimulated expression of collagen I and ACTA2 in MRC-5 cells (Figure E2). The results indicated that TAS-115 as well as nintedanib did not suppress the production of collagen I or ACTA2.
TAS-115 was reported to inhibit the phosphorylation of c-FMS in tumor cells (10, 18). We investigated the effect of this compound on M-CSF–induced c-FMS phosphorylation in BMDMs compared with nintedanib. TAS-115 inhibited the tyrosine phosphorylation of c-FMS at 10 nM, whereas 100 nM or more was needed for nintedanib to express similar inhibitory effects (Figures 2A and 2B). These results indicated that TAS-115 effectively suppressed the phosphorylation of c-FMS compared with nintedanib.
Figure 2. TAS-115 inhibits the phosphorylation of c-FMS on murine bone marrow–derived macrophages. (A) Bone marrow–derived macrophages were incubated with macrophage colony-stimulating factor (M-CSF) (100 ng/ml) with or without the indicated concentration (0–1,000 nM) of TAS-115 or nintedanib. The phosphorylation of c-FMS was determined by using a Simple Western system. (B) The relative intensity of phosphorylated c-FMS to c-FMS is shown (n = 3). *P < 0.01 versus groups treated with M-CSF without TAS-115 or nintedanib.
[More] [Minimize]Induction of CCL2 expression by the M-CSF–c-FMS axis contributes to the fibrotic changes in the lungs (12). CCL2 has been reported to be produced in the damaged lung (12, 19), and it regulates the recruitment and activation of fibrocytes and fibroblasts that express CCR2 (13, 20–22). One of the antifibrotic activities of pirfenidone, another clinically approved antifibrotic drug, is considered to be inhibition of the migration of fibrocytes via suppression of CCL2 production (23). Therefore, we hypothesized that inhibition of the phosphorylation of c-FMS by TAS-115 decreases CCL2 production in the lungs and thereby attenuates the fibrotic process. To confirm this, we evaluated whether TAS-115 inhibits M-CSF–dependent CCL2 production in BMDMs in vitro. As expected, M-CSF stimulation increased CCL2 production of BMDMs, and TAS-115 effectively inhibited CCL2 production at a lower dose than nintedanib (Figure 3A).
Figure 3. TAS-115 suppresses M-CSF–induced c-FMS production by bone marrow–derived macrophages. (A) M-CSF (100 ng/ml)–stimulated bone marrow–derived macrophages were cultured with the indicated concentration of TAS-115 or nintedanib for 24 hours (n = 4). The concentration of CCL2 in the culture supernatant was measured by ELISA. *P < 0.001 versus groups treated with PDGF-BB without TAS-115 or nintedanib. (B) TAS-115 (100 mg/kg/d), nintedanib (60 mg/kg/d), or vehicle was administered for 3 days starting at 7 days after a single transbronchial instillation of 3.0 mg/kg bleomycin (BLM). On Day 10, the mice were killed, and the BAL fluid was collected for further analyses (n = 6). (C and D) The concentrations of CCL2 and M-CSF in the BAL fluid were determined by ELISA. *P < 0.05, **P < 0.01, and ***P < 0.001. i.t. = intratracheal instillation; p.o. = by mouth.
[More] [Minimize]We next assessed the inhibitory effect of TAS-115 on the M-CSF–CCL2 axis in BLM-induced murine pulmonary fibrosis. TAS-115, nintedanib, or vehicle was administered for 3 days starting at 7 days after BLM treatment, and then the BALF was collected and analyzed to assess CCL2 or M-CSF concentration (Figure 3B). The concentration of CCL2 in BALF was increased by BLM treatment, which was consistent with previous reports using mouse models of infectious or noninfectious lung injury (12, 19). Administration of TAS-115 significantly reduced the concentration of CCL2 (Figure 3C) without affecting M-CSF concentration (Figure 3D). Meanwhile, treatment with nintedanib failed to suppress CCL2 expression. These results indicate that TAS-115 has a potent effect on inhibiting the M-CSF–CCL2 axis, but not M-CSF production, and this characteristic is not found in the pharmacodynamics of nintedanib in vivo.
To examine the antifibrotic effect of TAS-115 in vivo, we used a mouse model of BLM-induced pulmonary fibrosis. After receiving a single transbronchial instillation of 3.0 mg/kg BLM, the mice were treated daily with TAS-115 (30 or 100 mg/kg/d), nintedanib (60 mg/kg/d), or vehicle from Day 0. On Day 21, the mice were killed, and fibrotic changes in the lungs were assessed using the Ashcroft scoring system and a hydroxyproline assay. The histological findings of the lungs showed that BLM treatment induced inflammatory and fibrotic changes leading to an increased Ashcroft score and hydroxyproline content (Figure 4). The administration of TAS-115 significantly inhibited the histological changes and decreased both the Ashcroft score and hydroxyproline content at a dose of 30 mg/kg. A similar effect was observed when the mice were treated with nintedanib at 60 mg/kg.
Figure 4. TAS-115 attenuates BLM-induced lung fibrosis. Mice received a single transbronchial instillation of 3.0 mg/kg BLM on Day 0, and TAS-115 (30 or 100 mg/kg/d), nintedanib (60 mg/kg/d), or vehicle was administered daily from Day 0. Mice were killed, and their lungs were collected on Day 21. Lung sections were stained with (A) hematoxylin and eosin or (B) Azan-Mallory. (C) The fibrotic changes in the lungs were quantified with a numerical fibrotic score (Ashcroft score) histopathologically (n = 6). (D) Lungs were homogenized in distilled water, and the hydroxyproline contents were measured by hydroxyproline assay (n = 6). *P < 0.05 versus groups treated with BLM without TAS-115 or nintedanib; **P < 0.01 versus groups treated with BLM without TAS-115 or nintedanib; ***P < 0.001 versus groups treated with BLM without TAS-115 or nintedanib. Scale bars: 200 μm.
[More] [Minimize]Antifibrotic agents including nintedanib were reported to reduce the number of inflammatory cells and inflammatory cytokines in BALF of BLM-treated mice (24–26). Therefore, we next examined the cell counts and the cytokine profiles in the BALF collected at 7, 14, and 21 days after BLM instillation (Figures 5, E3, and E4). At both 14 and 21 days after BLM treatment, the concentration of TGF-β was lower in the TAS-115–treated group (100 mg/kg/d) than in the nintedanib-treated group (Figures 5 and E4B). Referring to the levels of inflammatory cytokines, TAS-115 inhibited the production of TNF-α more effectively than nintedanib, although the inhibitory effects of TAS-115 and nintedanib on IL-6 and IFN-γ production were similar (Figures 5 and E4B). The inflammatory cell counts in the BALF showed that both tyrosine kinase inhibitors decreased the numbers of lymphocytes at the both Day 14 and Day 21 as previously indicated in the experiment using nintedanib (Figures 5 and E4A) (24). On Day 7, there were no differences in cytokine profile and cell numbers by TAS-115 or nintedanib treatment (Figure E3). These data indicated that TAS-115 effectively suppressed proinflammatory and profibrotic cytokines contributing to lung fibrosis in the fibrotic phase.
Figure 5. Assessment of (A) cell counts and (B) cytokine expression in the BAL fluid of BLM-treated mice. Mice received a single transbronchial instillation of 3.0 mg/kg BLM on Day 0, and TAS-115 (30 or 100 mg/kg/d), nintedanib (60 mg/kg/d), or vehicle was administered daily from Day 0. Mice were killed, and the BAL fluid was collected on Day 14 (n = 6). *P < 0.05 versus groups treated with BLM without TAS-115 or nintedanib; **P < 0.01 versus groups treated with BLM without TAS-115 or nintedanib; ***P < 0.001 versus groups treated with BLM without TAS-115 or nintedanib.
[More] [Minimize]In the present study, we investigated the antifibrotic effects of a novel multiple tyrosine kinase inhibitor, TAS-115. TAS-115 clearly showed greater inhibitory activities on the phosphorylation of both PDGFR and c-FMS than nintedanib. The migration and proliferation of lung fibroblasts mediated by PDGF and the CCL2 production of macrophages induced by M-CSF were more strongly inhibited by TAS-115 than by nintedanib. The in vivo antifibrotic effects of TAS-115 were also demonstrated in the BLM-induced pulmonary fibrosis model.
Among several growth factors, the PDGF–PDGFR axis has consistently been reported to play important roles in suppressing lung fibrotic change by reducing the proliferation and migration of fibroblasts (2–4, 27, 28). In this study, TAS-115 showed lower IC50 values against PDGFR-α/β (IC50 = 0.81 ± 0.10/7.06 ± 0.83 nM), nearly equal values for VEGFR2 (IC50 = 30 ± 9 nM), and higher values for FGFR1 (IC50 > 970 nM), FGFR2 (IC50 = 340 ± 130 nM), and FGFR3 (IC50 > 940 nM), compared with the previously reported IC50 values of nintedanib (PDGFR-α/β, 59 ± 71/65 ± 7 nM; VEGFR2, 21 ± 13 nM; FGFR1/2/3, 69 ± 70/37 ± 2/108 ± 41 nM) (11, 29). These data suggest that TAS-115 strongly suppresses PDGF signaling in the local lung microenvironment and therefore may be a promising antifibrotic agent against IPF.
The roles of VEGFR and FGFR, the other molecules targeted by nintedanib, in pulmonary fibrosis are controversial. For instance, a VEGFR antagonist was reported to attenuate BLM-induced lung fibrosis in mice (30). Cao and colleagues reported that VEGFR1-expressing macrophages enhance lung fibrotic change by stimulating Notch signaling in fibroblasts (31). In a clinical study, Barratt and colleagues showed that the VEGF-A splice variant affects the development of pulmonary fibrosis (32). These findings suggest the profibrotic role of VEGF in pulmonary fibrosis. However, Murray and colleagues recently reported the protective role of VEGF during pulmonary fibrosis by modulating epithelial homeostasis (33). We could not assess the effect of TAS-115 on VEGF/VEGFR signaling in lung fibroblasts because the cell line we used (MRC-5 cells) did not express VEGFR; further study using primary fibroblasts and animal models would be required. In terms of the FGF–FGFR axis, the blockade of FGF signaling may show an antifibrotic effect via inhibition of the proliferation of fibroblasts (34). However, it may also worsen the excessive fibrotic changes in the lung by mechanisms such as the inhibition of epithelial repair (35–37). Furthermore, some FGFs, such as FGF1, have shown antifibrotic activities, including the inhibition of epithelial–mesenchymal transition, myofibroblast differentiation, and collagen production of fibroblasts (35, 38, 39). These results suggest that VEGF and FGF regulate the process of pulmonary fibrosis through diverse mechanisms and can be both pro- and antifibrotic. As such, careful attention is needed when developing antifibrotic agents that target these molecules. In this study, we showed that the IC50 value of TAS-115 for FGFR was higher than that of nintedanib, suggesting that TAS-115 may have a stronger antifibrotic effect.
Another considerable advantage of TAS-115 as an antifibrotic agent is that TAS-115 suppresses the phosphorylation of c-FMS more effectively than nintedanib. Although data of the precise IC50 of nintedanib for c-FMS were not described in previous articles, Tandon and colleagues showed that nintedanib inhibited the phosphorylation of c-FMS at the concentration of 300 nM (40). Together with our results, it is suggested that the IC50 of TAS-115 against c-FMS is lower than that of nintedanib. Regarding the significance of M-CSF in pulmonary fibrosis, Baran and colleagues reported that M-CSF aggravated fibrogenesis by inducing CCL2 production in the lung (12). This M-CSF–CCL2 axis may be a potential treatment target, and TAS-115 has potency for attenuating lung fibrosis via c-FMS blockade, resulting in the reduction of CCL2 expression.
TAS-115 also differs from nintedanib with regard to its suppressive effect against hepatocyte growth factor (HGF) signaling. Similar to nintedanib, TAS-115 was originally designed as a multi–tyrosine kinase inhibitor against cancer by targeting VEGFR, epidermal growth factor receptor, and HGF receptor (MET) (10, 18, 41). Thus, this drug was expected to have therapeutic potential against cancer, especially in those patients with bone metastasis and acquired resistance to cytotoxic agents by MET amplification. However, previous reports have indicated that enhanced HGF/MET signaling with HGF protein or gene transfer has a protective role in the pathogenesis of pulmonary fibrosis (42–45). Although the physiological role of HGF in the fibrogenesis of the lungs is still unclear, targeting MET may exacerbate pulmonary fibrosis. In the present study, TAS-115 exerted a significant antifibrotic effect, possibly due to the strong inhibition of PDGFR and c-FMS, and eliminating MET from the target might further enhance the efficacy of this drug.
Our study showed that TAS-115 attenuated BLM-induced lung fibrosis as we expected on the basis of its profile of kinase inhibition. BALF examination revealed that TAS-115 reduced the lymphocyte count and concentrations of proinflammatory and profibrotic cytokines in the fibrotic phase of BLM-treated mice, not in the acute inflammation phase. This phenomenon is consistent with our observation previously shown in antifibrotic effects of imatinib (4) and previous experiments assessing the antifibrotic effect of nintedanib (24), and it is considered to be a reflection of suppression of inflammation related to fibrotic change. Specifically, TAS-115 effectively suppressed the TNF-α and TGF-β expression more strongly than nintedanib (Figure 5). Because those cytokines are known to play critical roles in pulmonary fibrosis (46, 47), the favorable effect of TAS-115 on TNF-α and TGF-β expression further supports the usefulness of TAS-115 as an antifibrotic agent for pulmonary fibrosis. The expression of IL-6 was also inhibited in both tyrosine kinase inhibitor–treated groups, although the level of suppressive effects of TAS-115 and nintedanib on IL-6 was variable between Days 14 and 21, suggesting that these tyrosine kinase inhibitors affect late-phase inflammation related to fibrotic change, although they did not inhibit acute inflammation on Day 7.
In terms of safety, the results from a phase I study of TAS-115 in solid tumors revealed its good clinical tolerability, including a low frequency of severe diarrhea (grades 1–2, 14.3%; grades 3–4, 0%) (48), which is known to be a common problematic side effect of nintedanib (all grades, 62.4%) (7). In addition, TAS-115 has better bioavailability than nintedanib (maximum plasma concentration at 200 mg/d, 2,500–3,000 ng/ml for TAS-115 vs. 30–50 ng/ml for nintedanib) (44–46), suggesting that TAS-115 would effectively suppress the targeted receptors in patients with IPF.
In conclusion, TAS-115 has a preferable kinase inhibition profile that suppresses the PDGFR and c-FMS signaling pathways and attenuates BLM-induced lung fibrosis in mice. TAS-115 may be a new effective multiple kinase inhibitor for treating patients with pulmonary fibrosis via the strong inhibition of target molecules with favorable bioavailability. In the near future, the antifibrotic effects of TAS-115 will be demonstrated in an ongoing phase II clinical trial to evaluate its efficacy and safety for patients with IPF.
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Supported in part by the Practical Research Project for Rare Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) and by grants from the Ministry of Health, Labour and Welfare, Japan, awarded to the Study Group on Diffuse Pulmonary Disorders, Scientific Research/Research on Intractable Diseases and from Taiho Pharmaceutical (Y.N.).
Author Contributions: Conception and design: K. Koyama, H.G., S.S., H.K., Y.T., and Y.N.; analysis and interpretation: S.M., K. Kagawa, H.N., and H.O.; and drafting of the manuscript for important intellectual content: H.G., S.H., and Y.N.
This article has a data supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1165/rcmb.2018-0098OC on December 12, 2018
Author disclosures are available with the text of this article at www.atsjournals.org.
