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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2023, Vol. 17 Issue (2) : 275-289    https://doi.org/10.1007/s11684-022-0945-y
RESEARCH ARTICLE
A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma
Jing Yang1,2,3, Yanfei Yang1,4, Yuquan Wei1, Xiawei Wei1()
1. Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China
2. Melanoma and Sarcoma Medical Oncology Unit, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
3. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
4. Department of Gynecology and Obstetrics, The Third Xiangya Hospital, Central South University, Changsha 410008, China
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Abstract

The abnormal activation of HER family kinase activity is closely related to the development of human malignancies. In this study, we used HER kinases as targets for the treatment of nasopharyngeal carcinoma (NPC) and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B, alone or in combination with cisplatin. We found that HER family proteins were positively expressed in tumor tissues of some NPC patients, and the high levels of those proteins were significantly related to poor prognosis. HM781-36B inhibited NPC in vitro and in vivo. HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells. In NPC xenograft models in nude mice, HM781-36B and cisplatin synergistically inhibited tumor growth. Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin. In conclusion, our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC. The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients, which provides a new idea for the comprehensive treatment of NPC.
Keywords epidermal growth factor receptor      ErbB receptors      HM781-36B      nasopharyngeal carcinoma      molecular targeted therapy      cisplatin     
Corresponding Author(s): Xiawei Wei   
Just Accepted Date: 25 August 2022   Online First Date: 13 January 2023    Issue Date: 26 May 2023
 Cite this article:   
Jing Yang,Yanfei Yang,Yuquan Wei, et al. A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma[J]. Front. Med., 2023, 17(2): 275-289.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0945-y
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I2/275
Fig.1  Kaplan–Meier survival curves of progression-free survival (PFS) and overall survival (OS) in nasopharyngeal cancer patients with high and low expression of HER family proteins. (A) EGFR/HER1 protein expression in nasopharyngeal cancer tissues detected by immunohistochemistry staining, and representative images of low and high EGFR/HER1 expression tissues were shown (20×). All of the patients were divided into EGFR/HER1 low expression and high expression (interpreted independently by two pathologists; scores 0–5 were classified as low expression, and 6–12 were classified as high expression), and then Kaplan–Meier analysis were conducted. High expression of EGFR/HER1 was significantly associated with worse PFS and OS (log-rank P = 0.001, P = 0.006, respectively). (B) Representative images of low and high HER2-expressing tissues were shown (20×). High expression of HER2 was significantly associated with worse PFS and OS (log-rank P = 0.020, P = 0.014, respectively). (C) Representative images of low and high HER3-expressing tissues were shown (20×). High expression of HER3 was significantly associated with worse PFS and OS (log-rank P = 0.038, P = 0.008, respectively). (D) Representative images of low and high HER4-expressing tissues were shown (20×). High expression of HER4 was significantly associated with worse OS (log-rank P = 0.001), but not with PFS (log-rank P = 0.119). (E) Expression of HER family proteins in 5 nasopharyngeal carcinoma cell lines (purple, IgG; green, antibodies of HER family proteins).
Fig.2  HM781-36B and cisplatin synergistically inhibit the proliferation and colony formation abilities of nasopharyngeal carcinoma cells. (A) Cells were treated with increasing doses of HM781-36B (0 nmol/L, 100 nmol/L, 500 nmol/L, 1 μmol/L, 2 μmol/L, 3 μmol/L, 4 μmol/L, 5 μmol/L, 10 μmol/L) for 24, 48, or 72 h. The number of viable cells after treatment was measured by CCK-8 method and expressed as a percentage of viable cells. (B) C666-1 and CNE-1 cells were treated with increasing doses of HM781-36B for 48 h. Representative images showing the effects of HM781-36B on colony formation in C666-1 and CNE-1 cell lines. (C) The cells were treated with increasing doses of HM781-36B (0 nmol/L, 250 nmol/L, 500 nmol/L, 1 μmol/L, 2 μmol/L, 4 μmol/L) and cisplatin (0 nmol/L, 62.5 nmol/L, 125 nmol/L, 250 nmol/L, 500 nmol/L, 1 μmol/L) alone or their combination for 48 h, and the number of viable cells after treatment was measured by CCK-8 method and expressed as a percentage of viable cells. The combination index (CI) was determined using the Chou-Talalay method. CI < 1 indicates that the interaction between HM781-36B and cisplatin was synergistic. (D) Cells were treated with HM781-36B (2 μmol/L) or/and cisplatin (100 nmol/L) for 48 h. Representative images showing the effects of HM781-36B combined with cisplatin on colony formation of C666-1 and CNE-1 cell lines. *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001.
Fig.3  HM781-36B induces apoptosis and cell cycle arrest of nasopharyngeal carcinoma cells. (A) The C666-1 and CNE-1 cells were treated with increasing doses of HM781-36B for 48 h, and then the cells were stained with annexin V/PI and analyzed by flow cytometry. Data were shown as mean with SD. (B) The expressions of apoptosis-related proteins in C666-1 and CNE-1 cells treated with different concentrations of HM781-36B were detected by Western blot. β-actin was used as an internal control. (C) C666-1 and CNE-1 cells were treated with HM781-36B (1 μmol/L), cisplatin (1 μmol/L), or HM781-36B (1 μmol/L) combined with cisplatin (1 μmol/L) for 48 h, and then the cells were stained with annexin V/PI and analyzed by flow cytometry. (D) The effects of HM781-36B on cell cycle distribution of NPC cells were detected by flow cytometry. Data were shown as mean with SD. *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001.
Fig.4  HM781-36B inhibits cell migration, and the activation of HER and downstream signaling. (A,B) The migration capacity of CNE-1 cells was determined by wound healing assay, and wound length was imaged at the same location in each group at 0, 12, and 24 h. Scale bar = 100 μm. (C,D) C666-1 and CNE-1 cells were treated with increasing concentrations of HM781-36B for 48 h; HER family proteins and their downstream proteins were evaluated by Western blot. GAPDH was used as an internal control.
Fig.5  HM781-36B acts synergistically with cisplatin in inhibiting tumor growth in vivo. Tumor xenograft models were established by subcutaneously injecting 1 × 107 tumor cells into the right flank of female Balb/C nude mice. Mice were randomized into 5 groups (control, vehicle, cisplatin, HM781-36B, and combined therapy groups) before treatment at a point when tumors reached a volume of 150–200 mm3. HM781-36B was dissolved in 10% NMP, 10% Solutol, and 80% ddH2O. Cisplatin was dissolved in normal saline. Animals were given vehicle or HM781-36B (0.5mg/kg) once daily by oral gavage, and cisplatin was administered through intraperitoneal injection once a week (5 mg/kg). From the day of administration, body weight was recorded and tumor length and width were measured with caliper every three days. (A,D) Image of subcutaneous tumors of C666-1 (A) and CNE-1 (D) at the end of experiment. (B,E) Tumor volume change curve of C666-1 (B) and CNE-1 (E). (C,F) Weight of subcutaneous tumors in each group of C666-1 (C) and CNE-1 (F). Tumor volume was calculated as 0.52 × tumor length × tumor width2. Data were shown as mean with SEM. *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001. (G,H) Western blot was performed in xenograft tumors to detect the levels of HER family and their downstream proteins. Inhibition of p-EGFR/HER1, p-HER2, p-AKT, p-ERK, and p-STAT3 by HM781-36B alone or in combination with cisplatin was observed. GAPDH was used as an internal control.
Fig.6  HM781-36B exerts antitumor effects through inhibiting cell proliferation and promoting cell apoptosis. (A) Immunohistochemistry staining of tumor sections for the expression of Ki67 was performed. (B) Immunofluorescent staining of TUNEL of tumor sections was performed. (C) Representative images of hematoxylin and eosin (H&E) staining of tumors isolated from mice of vehicle and the drug-treated groups.
Fig.7  HM781-36B exerts antitumor effects through moderating tumor microenvironment. (A) Subcutaneous tumors of 3 mice in each group were randomly selected for staining (CD45, CD11b, F4/80, and CD206) and flow cytometry detection. After cisplatin treatment, the proportion of M2 macrophages (CD45+CD11b+F4/80+ CD206+) in tumor tissues was not statistically different from that in the control group. The proportion of M2 macrophages in tumor tissues treated with HM781-36B was significantly lower than that in the control group, and the proportion of M2 macrophages in the combined treatment group was significantly lower than that in other groups. (B) Frozen sections of subcutaneous tumor tissues from 3 mice in each group were randomly selected for immunofluorescent staining of F4/80 and CD206. Green fluorescent labeling is CD206 positive, red fluorescent labeling is F4/80 positive, and blue fluorescent labeling is nuclear DAPI. (C) Subcutaneous tumors of 3 mice in each group were randomly selected for staining (CD45, F4/80, CD11b, and CD11c) and flow cytometry detection. After cisplatin treatment, the proportion of DCs (CD45+F4/80–CD11b+CD11c+) in tumor tissues was statistically higher than that in the control group. The proportion of DCs in tissues of mice treated with HM781-36B was not statistically different from that in the control group, and the proportion of DCs in the tissues of combined treatment group was significantly higher than that in the control group. (D) Subcutaneous tumors of 3 mice in each group were randomly selected for staining (CD45, CD11b, and Gr-1) and flow cytometry detection. After cisplatin treatment, the proportion of MDSCs (CD45+CD11b+Gr-1+) in tumor tissues was significantly higher than that in the control group. The proportion of MDSCs in tumor tissues of mice treated with HM781-36B was significantly lower than that in the control group, and the proportion of MDSCs in the combined treatment group was not significantly different from that in the control group. Data were shown as mean with SEM. *P < 0.05, **P < 0.01, ***P < 0.001, **** P < 0.0001.
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