Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma

doi:10.1007/s11684-021-0869-y

Front. Med.

2022, Vol. 16

Issue (3) : 467-482 https://doi.org/10.1007/s11684-021-0869-y

RESEARCH ARTICLE

Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma

Chao Gao¹, Shenghao Wang¹, Weiqing Shao¹, Yu Zhang¹, Lu Lu¹, Huliang Jia¹, Kejin Zhu², Jinhong Chen¹, Qiongzhu Dong^1,³, Ming Lu¹, Wenwei Zhu¹(

), Lunxiu Qin^1,³(

)

¹. Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, Shanghai 200040, China
². Kanion Research Institute, Lianyungang 222002, China
³. Institutes of Biomedical Sciences, Fudan University, Shanghai 200040, China

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Abstract

Cabozantinib, mainly targeting cMet and vascular endothelial growth factor receptor 2, is the second-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, the lower response rate and resistance limit its enduring clinical benefit. In this study, we found that cMet-low HCC cells showed primary resistance to cMet inhibitors, and the combination of cabozantinib and mammalian target of rapamycin (mTOR) inhibitor, rapamycin, exhibited a synergistic inhibitory effect on the in vitro cell proliferation and in vivo tumor growth of these cells. Mechanically, the combination of rapamycin with cabozantinib resulted in the remarkable inhibition of AKT, extracellular signal-regulated protein kinases, mTOR, and common downstream signal molecules of receptor tyrosine kinases; decreased cyclin D1 expression; and induced cell cycle arrest. Meanwhile, rapamycin enhanced the inhibitory effects of cabozantinib on the migration and tubule formation of human umbilical vascular endothelial cells and human growth factor-induced invasion of cMet inhibitor-resistant HCC cells under hypoxia condition. These effects were further validated in xenograft models. In conclusion, our findings uncover a potential combination therapy of cabozantinib and rapamycin to combat cabozantinib-resistant HCC.

Keywords hepatocellular carcinoma cabozantinib primary resistance rapamycin

Corresponding Author(s): Wenwei Zhu,Lunxiu Qin

Just Accepted Date: 30 August 2021 Online First Date: 15 October 2021 Issue Date: 18 July 2022

Cite this article:

Chao Gao,Shenghao Wang,Weiqing Shao, et al. Rapamycin enhances the anti-tumor activity of cabozantinib in cMet inhibitor-resistant hepatocellular carcinoma[J]. Front. Med., 2022, 16(3): 467-482.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0869-y
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/467

Fig.1 Low expression of cMet is correlated with poor response of HCC cells to cabozantinib. (A) The expression of cMet, pMet (Y1234/1235), cyclin D1, and cleaved-PARP levels in Huh7 cells treated with cabozantinib (CAB, 2 or 4 μmol/L) or NZ001 (NZ, 2 or 4 μmol/L) was determined by Western blot analysis. (B) Cell survival curves of a panel of HCC cell lines treated with cabozantinib (CAB) or NZ001 (NZ) for 3 days were detected by CCK8 assay, and the IC50 values of cabozantinib and NZ001 are shown. (C) Drug response data (IC50) of HCC cell lines to cabozantinib in the Genomics of Drug Sensitivity in Cancer database are shown. (D) Representative images of IHC staining of cMet in 10 HCC samples. For patient 6, the areas labeled with black boxes in the left panel are shown in the right panels with higher magnification. Bar of left panel, 500 μm. Bar of right panels, 100 μm. For patients 5 and 8, bar, 200 μm. Data are shown as the mean±SD from three independent biological replicates.

Fig.2 Rapamycin can be used in combination with cabozantinib to inhibit the proliferation of cMet inhibitor-resistant HCC cells. (A) Percentage of living Huh7 and PLC cells after treatment with cabozantinib (CAB) alone or in combination with a panel of inhibitors for 3 days. The relative cell number of the control group was set as 100%; the three most effective inhibitors are marked in red. The significance was determined by one-way ANOVA (Bonferroni post test). (B–E) The phosphorylation levels of AKT (S473) (B), ERK (T202/Y204) (C), mTOR (S2448 and S2481) (D), and p65 (S536) (E) in Huh7 cells treated with the indicated inhibitors (MK2206 (AKTi), SCH772984 (ERKi), rapamycin (RAPA) (mTORi), and SC75741 (p65i)) or in combination with cabozantinib (CAB) were determined by Western blot analysis. Representative images from three independent experiments are shown.

Fig.3 Rapamycin sensitizes cMet-low HCC cells to cabozantinib. (A, B) The proliferation of Huh7 (A) and PLC (B) cells treated with cMet inhibitor (cabozantinib (CAB) or NZ001 (NZ)) and rapamycin (RAPA) alone or in combination at the indicated concentration for 3 days was measured using CCK8 assay. The significance was determined by two-way ANOVA (Bonferroni post test). (C, D) The CI of rapamycin (RAPA) and cMet inhibitor (cabozantinib (CAB) or NZ001 (NZ)) in inhibiting the proliferation of Huh7 (C) and PLC (D) cells was calculated using the Chou–Talalay method. (E, F) Colony formation assay of Huh7 and PLC cells treated with cMet inhibitor (cabozantinib (CAB, 2 μmol/L) or NZ001 (NZ, 2 μmol/L)) and rapamycin (RAPA, 10 nmol/L) alone or in combination for 14 days. Representative images (E) and bar charts of the colony numbers (F) are shown. For (F), the significance was determined by one-way ANOVA (Bonferroni post test). Data are shown as the mean±SD from three independent biological replicates. *P<0.05; **P<0.01; ***P<0.001; ns: not significant.

Fig.4 The combination treatment of cabozantinib and rapamycin shows enhanced anti-angiogenesis effect. (A, B) In the migration assay, 2 μmol/L of cabozantinib (CAB), 2 μmol/L of NZ001 (NZ), and 10 nmol/L of rapamycin (RAPA) alone or in combination were used to treat HUVECs. The representative images of scratches after 0 and 24 h (A) and the percentage of wound healing 24 h after scratching are shown (B). Bar, 200 μm. Data are shown as the mean±SD from three independent biological replicates. (C, D) Tubule formation assay of HUVECs treated with 2 μmol/L of cabozantinib (CAB), 2 μmol/L of NZ001 (NZ), and 10 nmol/L of rapamycin (RAPA) alone or in combination for 4 h. Representative images are shown (C), and the angiogenic index was calculated (D). Bar, 200 μm. Data are shown as the mean±SD from three independent biological replicates. (E, F) CD31 expression of subcutaneous implantation tumors from C57BL/6 mice treated with indicated inhibitors was detected by IHC staining. The representative images are shown (E), and CD31⁺ blood vessels per mm² were calculated accordingly (n = 6) (F). Bar, 100 μm. Data are shown as the mean±SD from six independent biological replicates. For (B), (D), and (F), the statistical significance was determined by one-way ANOVA (Bonferroni post test). *P<0.05, **P<0.01, ***P<0.001.

Fig.5 Combination treatment results in stronger inhibition of HGF-induced cell invasion of Huh7 cells under hypoxia condition. (A, C) Invasion assay of Huh7 cells treated with 1 or 10 ng/mL of HGF under normoxia or hypoxia condition for 48 h. The representative images are shown (A), and the chemotactic index was calculated as the ratio of the cell number of treatment groups to that of the control group (C). Bar, 100 μm. (B, D) The inhibitory effects of cabozantinib (CAB, 0.5 μmol/L and 1 μmol/L) alone or combined with rapamycin (RAPA, 10 nmol/L) on the invasion ability of Huh7 cells treated with 1 ng/mL of HGF under hypoxia condition were measured (B), and the chemotactic index was calculated (D). Bar, 100 μm. Data are shown as the mean±SD from three independent biological replicates. For (C) and (D), the statistical significance was determined by one-way ANOVA (Bonferroni post test). (E, F) The effects of rapamycin (RAPA) and cabozantinib (CAB) alone or in combination on tumor metastasis in lung metastasis models. The representative HE staining images of lung tissues (E) and the average numbers of lung metastatic lesions (F) from three mice per group are shown. Arrows indicate lung metastatic lesions, and the areas labeled with a black box in the upper panel are shown in the lower panel with higher magnification. Scale bar, 100 μm. For (F), data are shown as the mean±SD (n = 3), and the significance was determined by one-way ANOVA (Bonferroni post test). *P<0.05, **P<0.01, ***P<0.001.

Fig.6 Rapamycin augments the inhibitory effect of cabozantinib on the tumor growth of HCC xenograft in vivo. (A–C) Effects of rapamycin (RAPA) and cabozantinib (CAB) alone or in combination on tumor growth in subcutaneous xenograft models. Photos (A), tumor volume (B), and endpoint tumor weight (C) are shown. For (B) and (C), data are shown as mean±SD (n = 6). The significance was determined by two-way ANOVA (Bonferroni post test) (B) and one-way ANOVA (Bonferroni post test) (C). (D) The body weight of mice from different groups at day 1 (subcutaneous injection) and day 28 (mice sacrificed) was measured. Data are shown as mean±SD (n = 6). The significance was determined by one-way ANOVA (Bonferroni post test). (E–I) The expression of cyclin D1, PCNA, pmTOR (S2448), and pAKT (S473) in tumors from different experimental groups treated with the indicated inhibitors was detected by IHC staining. The representative images are shown (E). The IHC score of cyclin D1 (F), proliferation index based on the IHC score of PCNA (G), IHC score of pmTOR (S2448) (H), and IHC score of pAKT (S473) (I) are shown. Bar, 100 μm. HE, hematoxylin and eosin. For (F–I), data are shown as the mean±SD (n = 3), and the significance was determined by one-way ANOVA (Bonferroni post test). *P<0.05, **P<0.01, ***P<0.001; ns, not significant.

Fig.7 Combination treatment of cabozantinib and rapamycin leads to the suppression of RTK signaling downstream effectors and cell cycle arrest. (A, C) The inhibitory effect of cMet inhibitor (cabozantinib (CAB) or NZ001 (NZ)) and rapamycin (RAPA) alone or in combination on the phosphorylation of cMet (Y1234/1235) and downstream effectors AKT (S473), ERK (T202/Y204), mTOR (S2448), and P70S6K (T421/S424) (A) and on the expression of cyclin D1 (C) in Huh7 cells was analyzed by Western blot. (B, D) Huh7 cells treated with cMet inhibitor (cabozantinib (CAB) or NZ001 (NZ), 2 μmol/L) and rapamycin (RAPA, 10 nmol/L) alone or in combination were subjected to PI staining and assessed by flow cytometry (B). The percentage of Huh7 cells in each cell cycle stage was calculated (D). For (D), the statistical significance was determined by one-way ANOVA (Bonferroni post test). Data are shown as the mean±SD from three independent biological replicates. *P<0.05; ns, not significant.

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