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. 2025 Jan 16;116(4):951–965. doi: 10.1111/cas.16450

Multiple Kinase Small Molecule Inhibitor Tinengotinib (TT‐00420) Alone or With Chemotherapy Inhibit the Growth of SCLC

Hui Li 1,2, Chenchen Tang 1, Peiyan Zhao 2, Rui Zhong 2, Yuanhua Lu 3, Yan Liu 2, Rixin Li 1, Shaowei Lan 2, Chunjiao Wu 4, Xiaoyan Qiang 5, Peng Peng 5, Frank Wu 5, Ying Cheng 2,4,✉, Ying Liu 4,✉
PMCID: PMC11967258  PMID: 39817471

ABSTRACT

There is an urgent need to develop new targeted treatment agents for small cell lung cancer (SCLC). Tinengotinib (TT‐00420) is a novel, multi‐targeted, and spectrally selective small‐molecule kinase inhibitor that has shown significant inhibitory effects on certain solid tumors in preclinical studies. However, its role and mechanism of action in SCLC remain unclear. In this study, we demonstrated that tinengotinib effectively inhibited SCLC cell proliferation, especially highly expressing NeuroD1 (SCLC‐N), in the SCLC cell line‐derived xenograft (CDX) model and the malignant pleural effusion cell model of patients with SCLC. When combined with etoposide/cisplatin, it synergistically inhibited SCLC growth. Tinengotinib regulates proliferation, apoptosis, migration, cell cycle and angiogenesis in SCLC cells. Mechanistic studies revealed that c‐Myc expression may be a key factor influencing the effect of tinengotinib in SCLC‐N. This study provides reliable preclinical data and a new direction for tinengotinib as a promising therapy for SCLC, either alone or in combination with chemotherapy.

Keywords: aurora kinase, combination chemotherapy, novel multi‐targeted small molecule inhibitors, small cell lung cancer, targeted therapy

Tinengotinib, a multi‐targeted kinase inhibitor, demonstrates significant efficacy in inhibiting small cell lung cancer (SCLC) cell proliferation, particularly in the SCLC‐N subtype with high NEUROD1 expression. When combined with etoposide/cisplatin, it synergistically suppresses SCLC growth. The study suggests tinengotinib as a promising therapeutic option, either alone or in combination with chemotherapy, addressing the urgent need for improved treatments in SCLC.

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Abbreviations

AKI

aurora kinase inhibitor

AURK

aurora kinase

EP

etoposide and cisplatin

NSCLC

non‐small cell lung cancer

SCLC

small cell lung cancer

1. Introduction

Small cell lung cancer (SCLC) is a highly malignant lung cancer with a 5‐year survival rate of < 7% [1], and treatment predominantly relies on chemotherapy. Recent advances combining chemotherapy with immunotherapy have become the first‐line treatment for extensive‐stage SCLC (ES‐SCLC), significantly improving patient survival; however, the benefits are limited [2]. Strategies for targeted therapy in SCLC have undergone minimal changes over the past 30 years [3]. Therefore, molecular subtype‐based therapeutic strategies are urgently required for the treatment of SCLC.

Recent studies have classified SCLC into four subtypes based on transcription factor expression: SCLC‐A (ASCL1‐high), SCLC‐N (NeuroD1‐high), SCLC‐P (POU2F3‐high), and SCLC‐Y (YAP1‐high) [4, 5]. Drug sensitivity differs owing to differences in gene expression profiles [IMpower133 + CASPIAN (2022 AACR CT024)]. SCLC‐N, the most immunosuppressed subtype [6], is sensitive to aurora kinase inhibitors (AKIs) [4]. AKIs inhibited SCLC growth in preclinical studies. However, their clinical efficacy require further investigation, emphasizing the need for drug modifications and precise patient typing.

The aurora kinase family, including aurora kinase A (AURKA), AURKB, and AURKC, regulates the cell cycle from G2 to mitosis, with AURKA and AURKB playing crucial roles. Abnormal aurora kinase expression has been linked to tumorigenesis [7] in breast, ovarian, and lung cancers [8]. The AURKA inhibitor, LY3295668, significantly inhibited SCLC tumor growth [9]. Another AURKA inhibitor MLN8237 (alisertib), exhibited antitumor activity and synergistic effects with paclitaxel in SCLC cell lines and xenograft tumor models [10]. The AURKB inhibitor AZD1152 also inhibited SCLC proliferation in vivo and in vitro [11]. AKIs have also demonstrated antitumor activity in SCLC clinical trials but with varying degrees of toxicity. Alisertib monotherapy in a five‐arm phase II clinical trial achieved an objective response rate of 21% in 48 patients with SCLC, but exhibited significant toxicity [12]. A Phase I trial showed that alisertib combined with irinotecan induced intolerable hematologic and gastrointestinal toxicity in patients with SCLC [13, 14]. A randomized Phase II trial of MLN8237 as a second‐line treatment for SCLC showed significantly improved progression‐free survival (PFS) in c‐Myc‐positive SCLC, but no significant differences in PFS or median overall survival (OS) compared with the control group. The incidence of adverse events and the discontinuation rates were higher in the combination therapy group [10]. Moreover, in a Phase II clinical trial, the pan AKI PHA‐739358 exhibited a progression‐free rate of 0% at 4 months in patients with SCLC [13, 14]. Despite promising preclinical results, clinical trials have faced challenges, possibly due to the complex pathogenesis of SCLC, suggesting that a single target may not inhibit the clinical progression of SCLC.

Tinengotinib (TT‐00420) is an innovative, global phase III stage spectrum‐selective kinase inhibitor that exerts antitumor effects by targeting tumor cell proliferation, angiogenesis, and immune‐oncology pathways by inhibiting angiogenesis signaling (FGFRs and VEGFRs), mitotic kinases (AURKA/B), and immune‐related targets (JAK1/2). Ongoing clinical trials in the US and China have revealed the efficacy of tinengotinib against various solid tumors. It was granted the orphan drug designation (ODD) and fast track designation by the FDA for the treatment of cholangiocarcinoma (CCA), breakthrough therapy designation (BTD) by the National Medical Products Administration in China, and ODD for the treatment of tract cancer by European Medicines Agency. Preclinical studies have shown significant inhibitory effects against malignant tumors such as triple‐negative breast cancer (TNBC) and gallbladder cancer [15, 16]. A phase I clinical trial (NCT03654547) of TNBC and other solid tumors showed positive tolerability and pharmacokinetic parameters [15, 17]. A phase Ib/II clinical trial (NCT04742959) for solid tumors, including SCLC, showed that tinengotinib exhibited antitumor activity and was well tolerated in patients with advanced solid tumors who had received multiple treatments (2023 ASCO Annual Meeting) [18]. Considering the effectiveness of anlotinib [19], inhibition of multiple targets in the SCLC microenvironment may be an effective strategy.

In this study, we investigated the inhibitory effects of tinengotinib on SCLC growth in vivo and in vitro experiments. Its mechanism and influencing factors were validated in a cells from the malignant pleural effusion of patients with SCLC. This study explored the role of tinengotinib and the feasibility of using multi‐targeted small‐molecule inhibitors in combination with chemotherapy for SCLC. These findings provide a potential direction for research on new targeted drugs, addressing the current clinical limitations of SCLC treatment, and are supported by reliable research evidence.

2. Materials and Methods

SCLC cell lines were maintained under standard culture conditions. The experimental procedures included Database Screening, cell viability assays, cell cycle and apoptosis assays, western blotting, wound healing assays, in vivo xenograft studies, cellular transfection, culture pleural effusions and HE&IHC. Detailed information can be found in Data S1.

3. Results

3.1. Tinengotinib Inhibits SCLC Cell Proliferation

To investigate the inhibitory effect of tinengotinib on SCLC growth, we examined AURKA/B expression in common cancer cells using the CCLE (https://portals.broadinstitute.org/ccle/) and GEO (GSE149507) database. AURKA/B expression did not differ significantly among breast, lung, hepatocellular carcinoma, ovarian, and prostate cancer cells (Figure 1A). However, it was significantly higher in SCLC tissues (Figure 1B), suggesting that AURKA/B may be an effective therapeutic target for SCLC treatment. Tinengotinib significantly inhibited cell viability in various SCLC cell lines (H1092, H69, H2227, H446, SBC‐5, and H196), particularly H446 and H2227, showing the lowest IC50 (0.99 μg/mL and 0.98 μg/mL respectively) (Figure 1C). We examined the expression levels of vital transcription factors (ASCL1, NeuroD1, and YAP) in SCLC cells. This analysis confirmed that H446 and H2227 are SCLC‐N cells with high NeuroD1 (Figure 1D), consistent with previous reports [20], suggesting that SCLC‐N may exhibit greater sensitivity to tinengotinib.

FIGURE 1.

FIGURE 1

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Inhibitory effect of tinengotinib on the activity of SCLC cell lines. (A) Analysis of AURKA and AURKB mRNA expression in different tumor cell lines using CCLE dataset (n = 299). (B) Analysis of AURKA and AURKB mRNA expression in normal (n = 18) and tumor tissues (n = 18) of 18 SCLC patients using database GSE149507. (C) MTT assay to detect the inhibitory effect of different concentrations (0–51.2 μg/mL) of tinengotinib on cell viability for 48 h and its IC50 value in SCLC cell lines. (D) Western blot analysis for the expression levels of NeuroD1, ASCL1, and YAP in SCLC cells including H446, H2227 H69, H196, H1092, and SBC‐5. (E, F) MTT assay to detect the inhibitory effects of etoposide, cisplatin, anlotinib, and tinengotinib on cell viability and IC50 values of H446 (E) and H2227 (F). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Anlotinib is the only anti‐vascular small‐molecule multitarget inhibitor that has been clinically validated and applied in treatment of ES‐SCLC. Chemotherapy using cisplatin and etoposide (EP) is the cornerstone of ES‐SCLC treatment. We compared the IC50 values of etoposide, cisplatin, anlotinib, and tinengotinib in H446 and H2227 cells. Tinengotinib exhibited significantly lower IC50 values in H446 and H2227 cells, exhibiting over 50% reduction compared with anlotinib (Figure 1E,F). These results demonstrated that the inhibitory effect of tinengotinib on SCLC cell proliferation, particularly in SCLC‐N cells, surpasses etoposide, cisplatin, and anlotinib.

3.2. Tinengotinib Combined With Chemotherapy Synergistically Inhibits Proliferation and Migration in SCLC‐N Cells

To explore the potential effects of tinengotinib in combination with chemotherapy on SCLC‐N subtypes, we investigated the synergistic inhibitory effects of EP on the proliferation of SCLC‐N cells H446 and H2227 cells. Tinengotinib combined with EP significantly inhibited H446 cell viability (p = 0.0004), displaying a 10%–20% reduction compared to individual treatments (Figure 2A). In order to rule out the possible antagonistic effect of drugs at low concentrations, we selected tinengotinib (0.006–0.8 μg/mL), etoposide (0.06–1 μg/mL), and cisplatin (0.03–0.5 μg/mL) to examine the effects of drug combinations in H446 and H2227 cells. In H446 cells, the inhibitory effect of tinengotinib with EP was enhanced with increasing concentration. At 0.025, 0.1, 0.2, 0.4 and 0.8 μg/mL, tinengotinib with EP significantly inhibited cell viability compared to EP (p < 0.05). At 0.8 μg/mL, the combination significantly inhibited cell viability compared to the monotherapy group (p < 0.05) (Figure 2B). A similar trend was verified in H2227 cells, (Figure 2C,D). To investigate whether tinengotinib with EP had a synergistic effect in SCLC‐N cell lines, we increased the drug concentration (0.1–12.8 μg/mL), and the HSA method confirmed the synergistic effect in H446 cells (HSA score: 9.054) (Figure 2B). Similar synergistic effects were observed in H2227 cells (HSA score: 8.007) (Figure 2D). Tinengotinib with EP has a synergistic inhibitory effect on SCLC cell activity at the concentration from 0.1 to 2.8 μg/mL.

FIGURE 2.

FIGURE 2

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Tinengotinib synergizes with chemotherapy to inhibit SCLC‐N cell proliferation and migration. (A, C) MTT assay to detect the inhibitory effect of tinengotinib (0.1 μg/mL) with or without cisplatin (0.6 μg/mL) and etoposide (0.9 μg/mL) on the cell viability of H446 (A) and H2227 (C) cells. (B, D) MTT assay to detect the cell viability of tinengotinib (0.006–0.8 μg/mL) with or without cisplatin (0.06–1 μg/mL) and etoposide (0.03–0.5 μg/mL) in H446 (B) and H2227 (D) cells. Synergy plots show the occurrence of synergy (red), addition (white), or antagonism (green) of the different concentrations of tinengotinib and EP. Synergy scores were calculated with the HSA method using the SynergyFinder web application (3.0). (E, F) Wound healing ability and the relative migration rate of H446 (E) and H2227 (F) after 24 and 48 h treated with tinengotinib or combined with EP. Scale bar: 100 μm. *p < 0.05, **p < 0.01, ***p < 0.001. Each experiment was performed in triplicate. (G) Western blotting analysis on the expression of AURKA/B stable knockdown in H446 cells. (H) MTT assay to detect the cell viability of shNC, AURKA‐KD, or AURKB‐KD of H446 cells treated with EP. (I) Wound healing ability and the relative migration rate of shNC, AURKA‐KD, or AURKB‐KD of H446 treated with EP. (J) Apoptosis in shNC, AURKA‐KD, or AURKB‐KD of H446 cells treated with EP detected flow cytometry.

AURKA promotes cell migration [21, 22]. We investigated the migration ability of SCLC‐N cells using a scratch assay. Tinengotinib significantly decreased the migration rate of H446 cells at 24 h (p = 0.0005) and 48 h (p = 0.0013) compared with that in the control. The combination group also showed a significantly reduced migration rate at 24 h (p = 0.0021) and 48 h (p = 0.0041). The EP group showed a decreasing trend at 24 h and decreased significantly at 48 h (p = 0.0257) (Figure 2E). Similar results were observed in the H2227 cells (Figure 2F). To verify the synergistic effect of knockdown of AURKA or AURKB with EP, we transfected empty vector (shNC), AURKA shRNA (AURKA‐KD), or AURKB shRNA (AURKB‐KD) in H446 cells. Western blot confirmed that AURKA protein expression was reduced by 51% and AURKB by 98% compared to the parental cells (Figure 2G). With the treatment of EP, AURKA‐ KD or AURKB‐ KD cells synergistically decreased the cell viability (72% vs. 25%, 72% vs. 30%, respectively) and cell migration rate (30% vs. 0%, 30% vs. 8%, respectively) compared to the control group (Figure 2H,I). AURKA‐ KD or AURKB‐ KD cells synergistically up‐regulated the percentage of apoptosis (30% vs. 40%, 30% vs. 40%, respectively) (Figure 2J).

Overall, tinengotinib inhibited SCLC‐N cell migration and had a synergistic effect with EP in inhibiting SCLC‐N cell proliferation.

3.3. Tinengotinib Combined With EP Alleviates G2/M Phase Block and Promotes Apoptosis in SCLC‐N Cells

To understand the mechanism of tinengotinib‐induced SCLC‐N cell growth inhibition, we focused on the pivotal role of AURKA/B in cell cycle regulation [23, 24]. We examined the impact of tinengotinib on the cell cycle of H446 and H2227 cells and found that tinengotinib significantly increased the G2/M phase cells compared to the control group (p = 0.0109; p = 0.021). The G2/M and S phase cells in the EP group were significantly increased up to 75%. Notably, tinengotinib combined with EP decreased the G2/M phase cells to about 50%. The effect of tinengotinib on the cell cycle of H2227 was consistent with that of H446 (Figure 3A). These findings suggested that tinengotinib could arrest cells in the G2/M phase in H446 and H2227 and partially alleviate the G2/M phase block induced by EP. Thus, tinengotinib may impede EP‐induced cells from arresting in the G2/M phase and undergoing repair.

FIGURE 3.

FIGURE 3

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Tinengotinib combined with EP alleviates G2/M block and promotes apoptosis in SCLC‐N cells. (A) Tinengotinib (0.1 μg/mL) combined with cisplatin (0.6 μg/mL) and etoposide (0.9 μg/mL) on H446 and H2227 cells for 48 h. Cell cycle analysis in H446 and H2227 cells detected by flow cytometry. (B, C) Apoptosis in H446 (B) and H2227 (C) cells detected flow cytometry. The apoptosis rate was counted as a result of three experiments. (D) The changes in BCL2 and BAX expression in H2227 and H446 cells were detected by western blotting, and the bands were quantified by Image J software to calculate the BCL2/BAX ratio. *p < 0.05, ***p < 0.001.

We also evaluated the effect of tinengotinib combined with EP on apoptosis in SCLC‐N cells. Tinengotinib monotherapy and the combination treatment significantly increased apoptosis in H446 cells compared to that in the control group (p ≤ 0.001) (Figure 3B). However, there were no significant differences among the tinengotinib, EP, and combined groups. A similar trend was observed in the H2227 cells (Figure 3C). Western Blotting showed that in H446 cells, compared to the control group, both tinengotinib alone and in combination with EP reduced the BCL2/BAX ratio (a key molecular indicator for the regulation of apoptosis) to about 1/2. Similar results were observed in the H2227 cells (Figure 3D). These findings suggested that tinengotinib may modulate apoptosis in SCLC‐N cells via the BCL2/BAX dimer, thereby contributing to the inhibition of SCLC‐N cell growth.

3.4. Tinengotinib Alone or in Combination With EP Inhibits SCLC‐N Cell Angiogenesis

The highly vascularized nature of SCLC tumors poses treatment challenges [25]. Anlotinib, an anti‐vascular small‐molecule multi‐target inhibitor, has shown clinical success in treating SCLC [26, 27]. Tinengotinib is a multi‐targeted kinase inhibitor that targets angiogenesis related factors (FGFR and VEGFRs). Therefore, we established an in vitro system using HUVECs cultured alone or in combination with H2227 and H446 cells, to investigate the effects of tinengotinib on angiogenesis. The total segment length in the co‐cultured control group of H446 cells was significantly higher than that in the control group cultured (5500 vs. 4000) (p = 0.0068) (Figure 4A,B). Similar results were observed in H2227 cells (p = 0.046) (Figure 4C,D), suggesting that SCLC cells can promote angiogenesis.

FIGURE 4.

FIGURE 4

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Tinengotinib alone or in combination with EP inhibits SCLC‐N cell angiogenesis. (A, C) Tinengotinib, EP, or tinengotinib combined with EP was added to HUVEC cells or co‐culture with H446 and H2227 cells for 48 h. The formation of tubules was recorded in H446 cells (A) and H2227 cells (C). (B, D) The mesh index and segment length of HUVEC cells in H446 co‐culture system (B) and H2227 co‐culture system (D). Scale bar: 100 μm. Tubule length and mesh index were analyzed by Image J. The results of three experiments were statistically obtained, *p < 0.05, **p < 0.01, ***p < 0.001, ****, p < 0.0001.

In the HUVEC alone culture group, tinengotinib, EP, or their combination significantly reduced the mesh index to < 1/3 and the total segment length to < 1/8 of the control. In the H446 co‐culture system, tinengotinib down‐regulated both the mesh index and total segment length to < 1/2 of the control group, similar results were observed in the EP or the combination group. Notably, a synergistic inhibitory effect was observed on the total segment length in the combination treatment (Figure 4B), and similar results were observed in H2227 cells (Figure 4D). These results suggested that tinengotinib can significantly inhibit angiogenesis, especially in SCLC, with a potential synergistic inhibitory effect when combined with EP.

3.5. Tinengotinib Alone or in Combination With EP Inhibits SCLC Growth and Patient Malignant Pleural Effusion Cell Proliferation In Vivo

To verify the inhibitory effect of tinengotinib on SCLC growth in vivo, we subcutaneously injected H446 cells into NOD‐Scid mice to establish a xenograft models of SCLC. Treatment with tinengotinib, EP, or their combination significantly reduced tumor volume compared to the control group (p < 0.0001) (Figure 5A). Tinengotinib and EP combination synergistically suppressed the tumor volume compared to tinengotinib or EP aone (p < 0.0001) (Figure 5A). However, mice treated with EP or the combination showed decreased body weight compared to the tinengotinib group (Figure 5B), which was likely due to the more potent side effects of EP. Remarkably, tumors treated with tinengotinib maintained a static growth without adverse effects on body weight during the 35‐day treatment period (Figure 5B). Images of mouse tumors also confirmed the synergistic effects of tinengotinib combined with EP on tumor reduction. Tinengotinib alone significantly decreased the tumor size compared to the control, with fewer intra‐group differences. Although there were more deaths in the EP group and combination treatment groups, the tumors were smaller in the combination group than in the EP or tinengotinib monotherapy groups (Figure 5C). We further examined the CD31‐positive angiogenesis in mouse tumor tissues and found that tinengotinib, EP, or their combination could inhibit angiogenesis in the SCLC microenvironment. Compared to the microvascular density (MVD) value of 15 in the control group, that of the tinengotinib group decreased to about two. In the EP group, this decreased to around eight. In the combination treatment group, it decreased to about three (Figure 5D). These findings demonstrated that tinengotinib significantly inhibits angiogenesis in the SCLC microenvironment in vivo. In Addition, we collected malignant pleural effusions from two SCLC patients (Table 1). The cell sediment was collected after 48 h, including the primary cells and spheroids (a primary form of organoid) and treated with different concentrations of tinengotinib (0.1 μmol/mL, 0.2 μmol/mL, and 0.4 μmol/mL), EP, and 0.1 μmol/mL tinengotinib combined with EP. As shown in Figure 5D,E, the results indicate that tinengotinib, EP, and their combination significantly inhibited the proliferation of primary SCLC pleural effusion cells. Notably, 0.1 μg/mL tinengotinib with EP showed a more substantial effect than 0.1 μg/mL tinengotinib alone (p = 0.0363) (Figure 5D).

FIGURE 5.

FIGURE 5

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Tinengotinib alone or in combination with EP in preclinical tumor models. (A, B). Tumor volume (A) and body weight (B) were measured in xenografts of H446 cells injected subcutaneously in the flank of 5–6 weeks old male NOD‐Scid mice (n = 5/group). Tumor‐bearing mice were treated with tinengotinib, EP, or tinengotinib combined with EP, respectively. Data are expressed as mean ± SEM. (C) The pictures of Nod‐Scid mice and subcutaneous tumors were taken on the 35th day after treatment. (D) Representative images of immunohistochemistry (IHC) staining for CD31 in xenograft tumors derived from H446 cells. The endothelial cells of blood vessels were stained for CD31 (red arrows). Five fields of view were selected for microvessel (MVD) counting at 400× magnification. Scale bar = 100 μm. *p < 0.05, **p < 0.01, ***p < 0.001. (E, F) Primary cells and spheroids were isolated and cultured from pleural effusions from two SCLC patients. These cells were treated with tinengotinib, EP, or tinengotinib combined with EP for 48 h (40×), and detected the cell viability. Scale bar: 100 μm. The results from three experiments were statistically obtained, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.

TABLE 1.

Patient characteristics of the malignant pleural effusions from SCLC patients.

Age, years Gender Stage Smoking Diagnosis
65 Male T4N3M1 IV Current SCLC
61 Male T4N2M0 IIIB Current SCLC
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Overall, tinengotinib significantly inhibited the growth of SCLC tumors in vivo without affecting mouse survival, and its efficacy was enhanced when combined with EP.

3.6. C‐Myc May Be a Key Factor Influencing the Therapeutic Efficacy of Tinengotinib

The response to tinengotinib varied among the different SCLC cell lines (Figure 1C). Previous studies have indicated that SCLC cells with high NeuroD1 expression are sensitive to AKIs [4]. To explore the determinants of tinengotinib sensitivity, we examined the expression of transcription factor proteins in different SCLC cell lines. NeuroD1 expression was high in both sensitive (H2227, H446) and less sensitive (H69) cells (Figure 1D), suggesting that NeuroD1 may not be the primary determinant of SCLC sensitivity to tinengotinib. To investigate the correlations of the levels of AURKA and AURKB with the sensitivity/resistance to tinengotinib, the expression levels of AURKA/B were analyzed in SCLC cell lines, including H446, H2227, H69, H196, H1092 and SBC‐5 (Figure 6A). We analyzed the correlation between protein expression of AURKA/AURKB and the IC50 of tinengotinib in SCLC cell lines. It showed that AURKA (p = 0.8331) and AURKB (p = 0.5085) were not correlated with tinengotinib sensitivity (Figure 6B). To further investigate the effect of AURKA/B expression on the antitumor activity of tinengotinib in SCLC‐ N cell lines, AURKA/B was knocked down in H446 (Figure 6C) and H2227 (Figure 6E) cells to detect the antitumor activity of tinengotinib. Compared to the control group, IC50 of tinengotinib in H446 with AURKA/B knockdown was significantly increased (p = 0.0165; p = 0.0007) (Figure 6D). However, H2227 showed an increasing trend in IC50 values, but this was not statistically significant (p = 0.12; p = 0.17). Therefore, we speculated that the expression of AURKA/B might not be the only factor affecting the sensitivity to tinengotinib.

FIGURE 6.

FIGURE 6

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c‐Myc may be a key factor influencing the therapeutic efficacy of tinengotinib. (A) Western blotting analysis on AURKA/B expression in SCLC cell lines. (B) The correlation between protein expression of AURKA/AURKB and the IC50 tinengotinib in SCLC cell lines. (C, E) Western blotting analysis on the expression of AURKA/B knockdown in H446 (C) and H2227 (E) cells. (D, F) The cell viability of tinengotinib (0–12.8 μg/mL) in H446 (D) and H2227 (F) cells with knockdown Aurora A/B expression by MTT assay. (G) Western blotting analysis on c‐Myc expression in SCLC cell lines. (H) The cell viability of tinengotinib (0.8 μg/mL) in H446 and H2227 cells with c‐Myc knockdown. (I, J) The cell viability of tinengotinib(0–12.8 μg/mL) in H446(I) and H2227(J) cells with c‐Myc knockdown by MTT assay. (K) Western blotting analysis on the expression of NeuroD1 in c‐Myc knockdown. The expression of ASCL1, NeuroD1, YAP1, and c‐Myc in H446 and H2227 cells treated with tinengotinib, EP, and tinengotinib combined with EP for 48 h. The bands were quantified by Image J software. (L) Representative images of H&E and immunohistochemistry (IHC) staining for c‐Myc and CD31 in xenograft tumors derived from H446 cells. C‐Myc expression was quantified by the Image J software for quantitative analysis. CD31 was quantified at 400× magnification, and five fields of view were selected for microvessel (MVD) counting, Scale bar = 100 μm. *p < 0.05, **p < 0.01, ***p < 0.001.

MYC amplification is a biomarker of the efficacy of AKIs [4, 28, 29]. We determined the expression of c‐Myc in all SCLC cell lines (H446, H2227, H69, H196, H1092, and SBC‐5) and found that it was expressed in all tested SCLC cell lines (Figure 6G). To investigate the correlation between c‐Myc expression and the antitumor activity of tinengotinib, c‐Myc was overexpressed in H446 and H2227 cells. The cell survival rate decreased from 50.98% to 39.45% in the overexpressed cells under tinengotinib treatment (Figure 6H). Knocking down c‐Myc in H446 showed the IC50 of tinengotinib (8.54 μg/mL) was significantly increased compared to the control (0.99 μg/mL) (p = 0.0043) (Figure 6I). The same trend was observed in H2227 (p = 0.0343) (Figure 6J). Therefore, we speculated that the sensitivity of SCLC cells to tinengotinib may be related to c‐Myc expression.

We noted that the SCLC‐N cell lines were more sensitive to tinengotinib. To verify whether c‐Myc expression affects anti‐tumor sensitivity by regulating NeuroD1 expression, we explored the relationship between c‐Myc and NeuroD1 expression in SCLC‐N cell lines. Data showed that NeuroD1 expression was decreased when knocked down c‐Myc in H446 and H2227 cells (Figure 6K). It has been reported that in neuroendocrine cells, MYC activation promotes SCLC from ASCL1+ to NeuroD1+ to YAP1+ [30]. Therefore, we speculated that the anti‐tumor activity of tinengotinib might be regulated by modulating the c‐Myc‐NeuroD1 axis in SCLC‐N cells. These results suggested that c‐Myc may be pivotal in modulating the efficacy of tinengotinib. Furthermore, Western Blotting results showed significant downregulation of c‐Myc after tinengotinib combined with EP treatment in H446 or H2227 cells (Figure 6K). Immunohistochemistry of mouse model tumors confirmed that the lowest c‐Myc expression in the tinengotinib combined with EP group compared to other groups was significantly lower than the control group (p = 0.02) (Figure 6L). These findings suggest that c‐Myc may play a pivotal role in regulating the efficacy of tinengotinib against SCLC.

4. Discussion

Tinengotinib is an innovative, global phase III stage spectrum‐selective kinase inhibitor it exerts antitumor effects through multiple targets. In this study, we examined its inhibitory effects on various phenotypes of SCLC cells. In vitro and in vivo experiments, including patient‐derived samples, confirmed its anti‐tumor effects on SCLC. Particularly, when tinengotinib was combined with EP, marked synergistic effects were observed in SCLC‐N cells. In vitro experiments revealed that tinengotinib modulated various cellular processes such as cell proliferation, cycling, apoptosis, migration, and angiogenesis. In NOD‐Scid mouse models with SCLC cell line‐derived xenograft (CDX) and primary cells derived from malignant pleural effusions of SCLC patients, tinengotinib alone or with EP effectively inhibited the growth of SCLC‐N cells. Notably, tinengotinib exhibited minimal toxicity. These results highlighted the potential of tinengotinib for treating SCLC, particularly the SCLC‐N subtype, suggesting its viability as a safe monotherapy (Figure 7).

FIGURE 7.

FIGURE 7

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Graphical Table of Content. Tinengotinib (TT‐00420) is a novel, spectrum‐selective kinase inhibitor targeting angiogenesis (FGFRs and VEGFRs), mitotic kinases AURKA/B, and immune‐related targets JAK1/2. Our study investigated the anti‐tumor effects of tinengotinib alone or in combination with EP using in vitro and in vivo experiments. In vitro, tinengotinib modulated cell proliferation, cycling, apoptosis, migration and angiogenesis. When combined with EP, it showed synergistic inhibition in SCLC‐N cells. The anti‐tumor activity may be regulated by the c‐Myc‐NeuroD1 axis. In vivo experiments using the SCLC CDX model in NOD‐Scid mice demonstrated that tinengotinib significantly inhibited the growth of SCLC tumors, and tinengotinib with EP had a synergistic and improved inhibitory effect.

SCLC is widely recognized as a refractory tumor with limited treatment options [31, 32]. Anlotinib, a small‐molecule and multi‐targeted tyrosine kinase inhibitor with angiogenesis and tumor growth inhibiting, is currently the only targeted drug currently effective for second‐line SCLC treatment [19, 33]. The efficacy of anlotinib may be attributed to its effects on multiple targets, thereby effectively modulating the complex pathogenesis of SCLC. Similarly, tinengotinib is an innovative spectrum‐selective kinase inhibitor [34] that exerts antitumor effects by targeting tumor cell proliferation, angiogenesis (FGFR1/2/3 and VEGFRs), mitotic kinases AURKA/B and JAK [15]. Tinengotinib has shown high efficacy in treating TNBC, prostate cancer, HR+/HER2− BC, and CCA. It inhibits the growth of gallbladder cancer cell lines with a low IC50, particularly by targeting FGFR1 and its downstream pathway JNK/JUN in vitro CDX model [16].

Database searches have revealed higher expression of AURKA/B, one of the main targets of tinengotinib, in SCLC tissues than in control tissues. Our study confirmed that tinengotinib significantly inhibited SCLC cell proliferation and tumor growth in NOD‐Scid mice, consistent with previous studies, showing greater efficacy than chemotherapy or anlotinib treatment. Tinengotinib also inhibited the migration of SCLC cells to a greater extent than did EP. Multi‐targeted antitumor drugs generally exhibit superior efficacy, reduced drug resistance and fewer toxic side effects than single‐target drugs [35]. It has been found that the “one‐two punch” therapeutic strategy can inhibit its growth in breast cancer [36]. In our study, tinengotinib showed lower toxicity and a more substantial tumor‐suppressive effect in combination with EP. The notable effects of both EP and EP combined with tinengotinib on the body weight of mice could be attributed to the toxicity of EP. A previous study has reported the effects of different combinations of EP dosage combinations in KSN nude mice treated with endometrial cancer. For instance, cisplatin (5 mg/kg) + etoposide (10 mg/kg) resulted in a 7.8% reduction in body weight, and cisplatin (7.5 mg/kg) + etoposide(10 mg/kg) led to a weight loss of up to 8.9%. However, the body weight recovered rapidly after the completion of the chemotherapy [37]. Notably, when cisplatin was administered at 10 mg/kg, 10 of the 22 mice became emaciated and died within 2 weeks, whereas the remaining 12 mice showed a maximum weight loss of 14.7% [37]. These findings suggest that EP dramatically affected the body weight and survival of mice. Similarly, in a study involving lung cancer, cisplatin (5 mg/kg) or etoposide (5 mg/kg) in BALB/c mice resulted in a severe reduction in body weight (down to 17 g) within 21 days compared to the initial body weight at the start of treatment (20 g) [38]. Although the doses of cisplatin (3 mg/kg) and etoposide (8 mg/kg) used in our study were lower than those studies, more suitable dosages for EP combination therapy should be explored. Nevertheless, our study demonstrated that tinengotinib inhibits SCLC growth, and its combination with EP exhibits a notable trend of synergistic inhibition of SCLC growth. The mechanism of tinengotinib in SCLC cells is different from that of chemotherapy. Etoposide, a DNA synthesis inhibitor, induces cell death by forming complexes with topoisomerase II and DNA, resulting in double‐stranded DNA breaks [39, 40]. Both EP and tinengotinib effectively inhibited the migratory ability and proangiogenic effects in SCLC‐N cells.

Different SCLC subtypes exhibit different characteristics and drug sensitivities [4, 41]. AURKA kinase inhibition combined with PD‐L1 immunotherapy showed durable efficacy in SCLC mouse models and reduced ASCL1 expression, suggesting that the efficacy of Aurora A kinase inhibitors may be related to ASCL1 expression [42]. In breast and ovarian cancer cells, decreasing the expression of YAP/TAZ expression increased the sensitivity to the AURKA inhibitor MLN82373 [43]. In lung cancer cells A549, with an increased dose of the AURKA kinase inhibitor VX680, the expression level of YAP protein was decreased significantly [44]. We also observed that tinengotinib reduced YAP expression in H446 and H2227 cells (Figure 6K). The effect of YAP on the antitumor activity of the AKIs needs further investigation. Our study confirmed that SCLC‐N cells expressing high levels of NeuroD1 are more sensitive to tinengotinib. Consistent with previous reports, SCLC‐N cells were highly sensitive to multiple AKIs [4]. However, non‐SCLC‐N cells, such as H69, SBC‐5 and H196 cells [20], with lower NeuroD1 expression, displayed much lower sensitivity to tinengotinib. This finding suggests that NeuroD1 expression may not be the primary determinant of tinengotinib sensitivity. We also found that AURKA/B might not be the only factor influencing tinengotinib sensitivity, possibly because tinengotinib affects the antitumor activity of SCLC by regulating multiple targets, as well as because of the complex tumor heterogeneity of SCLC tumors, which has been observed with other drugs. For example, PARP1 expression was not correlated with PARP inhibitor sensitivity in 24 human SCLC cell lines [45]. In a phase II clinical study using PARP inhibitors for recurrent SCLC, PARP1 expression did not show correlation with clinical efficacy [46].

Notably, c‐Myc overexpression increased the sensitivity of SCLC cells to tinengotinib. Interestingly, c‐Myc expression was altered after drug treatment, suggesting its potential role as a regulatory factor. Further investigation is necessary to explore c‐Myc as a predictive biomarker of therapeutic efficacy. Li et al. reported that the AURKA inhibitor, MLN8237 could destabilize the c‐Myc protein in tumor cells by disrupting the c‐Myc/AURKA complex [47], highlighting the potential for modifying c‐Myc expression through targeted therapy. This emphasizes the importance of further studies to determine predictive biomarkers of tinengotinib efficacy.

Targeted therapy for SCLC is limited because of its complex and heterogeneous pathogenesis. Our study demonstrated that the novel multitargeted small‐molecule kinase inhibitor tinengotinib could significantly inhibited SCLC growth. Moreover, the combination of tinengotinib and chemotherapy enhanced its efficacy. This opens a new direction for targeted therapeutic drug research and provides a potential combination treatment option for SCLC. Our findings offer promising the development targeted therapy in SCLC.

Author Contributions

Hui Li: conceptualization, project administration, supervision, writing – review and editing. Chenchen Tang: data curation, formal analysis, visualization, writing – original draft, writing – review and editing. Peiyan Zhao: supervision, visualization, writing – review and editing. Rui Zhong: methodology, validation. Yuanhua Lu: data curation, validation. Yan Liu: data curation. Rixin Li: formal analysis. Shaowei Lan: data curation. Chunjiao Wu: resources. Xiaoyan Qiang: resources, writing – review and editing. Peng Peng: resources. Frank Wu: resources. Ying Cheng: funding acquisition, project administration, supervision. Ying Liu: conceptualization, funding acquisition, project administration.

Ethics Statement

Approval of the Research Protocol by an Institutional Review Board. This study was approved by the Ethics Committee of Jilin Cancer Hospital, China.

Consent

Each patient was required to provide informed consent before implementing the study, which was performed by the ethical guidelines of the Declaration of Helsinki of 1975.

Conflicts of Interest

The authors declare no conflicts of interest.

Registry and the Registration No. of the Study/Trial

The authors have nothing to report.

Animal Studies

All the animal experimental protocols were approved by the Ethics Committee for Animal Experiments of the First Hospital of Jilin University (grant number 20210913).

Supporting information

Data S1.

CAS-116-951-s001.docx (27.1KB, docx)

Acknowledgments

The authors have nothing to report.

Funding: This work was supported by the Department of Science and Technology of Jilin Province (202002062JC; 20210204031YY; YDZJ202201ZYTS189); National Cancer Center (NCC201907B02; NCC201907B01); the Scientific Research Funds of Jilin Province of Health and Family Planning Commission (2021JC096).

Hui Li and Chenchen Tang have contributed equally to this work.

Contributor Information

Ying Cheng, Email: chengying@csco.org.cn.

Ying Liu, Email: yingliu700930@foxmail.com.

Data Availability Statement

The data supporting the findings of this article are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Data S1.

CAS-116-951-s001.docx (27.1KB, docx)

Data Availability Statement

The data supporting the findings of this article are available from the corresponding author upon reasonable request.

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