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Dasatinib in combination with BMS-754807 induce synergistic cytotoxicity in lung cancer cells through inhibiting lung cancer cell growth, and inducing autophagy as well as cell cycle arrest at the G1 phase

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Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. Combination of drugs targeting independent signaling pathways would effectively block the proliferation of cancer cells with lower concentrations and stronger synergy effects. Dasatinib, a multi-targeted protein tyrosine kinase inhibitor targeting BCR-ABL and kinases of SRC family, has been successfully applied in the treatment of chronic myeloid leukemia (CML). BMS-754807, an inhibitor targeting the insulin-like growth factor 1 receptor (IGF-IR) and insulin receptor (IR) family kinases, has been in phase I development for the treatment of a variety of human cancers. Herein, we demonstrated that dasatinib in combination with BMS-754807 inhibited lung cancer cell growth, while induced autophagy as well as cell cycle arrest at the G1 phase. Dasatinib in combination with BMS-754807 suppressed the expression of cell cycle marker proteins, Rb, p-Rb, CDK4, CDK6 and Cyclin D1, and the PI3K/Akt/mTOR signaling pathway. Dasatinib in combination with BMS-754807 induced autophagy in lung cancer cells, evidenced by the upregulation of LC3B II and beclin-1, the downregulation of LC3B I and SQSTM1/p62, and the autophagic flux observed with a confocal fluorescence microscopy. Furthermore, dasatinib (18 mg/kg) in combination with BMS-754807 (18 mg/kg) inhibited the growth of tumors in NCI-H3255 xenografts without changing the bodyweight. Overall, our results suggest that dasatinib in combination with BMS-754807 inhibits the lung cancer cell proliferation in vitro and tumor growth in vitro, which indicates promising evidence for the application of the drug combination in lung cancer therapy.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 30901821 and 81172136), Natural Science Basic Project of Shanxi Province, China (No. 20210302124183), Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (No. 2021L339), Nature Science Project of Shanxi Province, China (Nos. 201701D121165 and 201901D111190), Natural Science Foundation for Young Scientists of Shanxi Province, China (No. 201801D221069), Research Project Supported by Shanxi Scholarship Council of China (Nos. 2020 − 194 and 2021 − 165), Open Fund from Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, China (No. KLMEC/SXMU-202011), Shanxi ‘1331 Project’ Key Subjects Construction, China (No. 1331KSC), Outstanding Youth Foundation of Shanxi Province, China (No. 201901D211547), Scientific research project of Shanxi Provincial Health Commission, China (No. 2019059), “136” College-level open fund, China (No. 2021YZ03).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, 030001, China

    Chan Zhang, Xinan Zhao, Zifeng Wang, Tao Gong, Hong Zhao, Dong Zhang, Yuhu Niu, Xiaoning Li, Xuhua Zhao & Baofeng Yu

  2. Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China

    Chan Zhang

  3. General Surgery Department, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China

    Gaopeng Li & Xiushan Dong

  4. Department of General Surgery, The First Hospital of Shanxi Medical University, Taiyuan, 030001, China

    Li Zhang & Jun Xu

  5. Department of Biochemistry and Molecular Biology, Changzhi Medical College, Changzhi, 046000, China

    Chang Liu

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  1. Chan Zhang
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Contributions

Conceived and designed the experiments: CZ, CL, BY. Performed the experiments: CZ, XZ, ZW. Analyzed the data: CZ, CL. Contributed reagents/materials/analytical tools: CZ, XZ, ZW, TG, HZ, DZ, YN, XL, XZ, GL, XD, LZ, JX. Wrote the paper: CZ, CL, BY.

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Correspondence to Chang Liu, Jun Xu or Baofeng Yu.

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Zhang, C., Zhao, X., Wang, Z. et al. Dasatinib in combination with BMS-754807 induce synergistic cytotoxicity in lung cancer cells through inhibiting lung cancer cell growth, and inducing autophagy as well as cell cycle arrest at the G1 phase. Invest New Drugs 41, 438–452 (2023). https://doi.org/10.1007/s10637-023-01360-9

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