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Antiemetic drug fosaprepitant exerts anti-tumor effects against NSCLC by targeting FAK to inhibit AKT and JNK/c-Jun pathways

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Non-small cell lung cancer (NSCLC) is an aggressive malignancy with a poor prognosis. Abnormal expression of focal adhesion kinase (FAK) is closely linked to NSCLC progression, highlighting the need for effective FAK inhibitors in NSCLC treatment. In this study we conducted high-throughput virtual screening combined with cellular assays to identify potential FAK inhibitors for NSCLC treatment. Fosaprepitant (FOS), a clinical antiemetic drug, exhibited a high affinity for FAK with a KD value of 4.35 × 10⁻⁵ M. The direct interaction between FOS and FAK was confirmed by molecular docking, molecular dynamics, drug affinity responsive target stability and surface plasmon resonance analysis. We showed that FOS (15, 25 μM) dose-dependently inhibited the proliferation, migration and invasion of A549 and H1299 cells by targeting FAK. The IC50 values in inhibiting the cell viability at 24 h were 73.05 and 126.1 μM, respectively. Knockdown FAK reversed the inhibitory effects of FOS on A549 cells. Using RNA sequencing and Western blotting analysis, we demonstrated that FOS treatment led to downregulation of the AKT and JNK/c-Jun signaling pathways in A549 and H1299 cells. Importantly, point mutation analyses revealed that FOS primarily targeted the Y925 phosphorylation site on FAK. In A549 cells xenograft nude mouse model, administration of FOS (20, 60 mg/kg, i.p. every 2 d for 2 weeks) dose-dependently suppressed the tumor growth. Collectively, FOS exhibits significant anti-NSCLC activity both in vitro and in vivo by binding to FAK and inhibiting its phosphorylation, thereby blocking the AKT and JNK/c-Jun signaling pathways. These results suggest FOS as a novel FAK inhibitor for NSCLC treatment.

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Fig. 1: Identification of FOS as a FAK inhibitor via Virtual Screening (VS).
Fig. 2: FOS suppresses the proliferation of NSCLC cells by targeting FAK.
Fig. 3: FOS inhibits NSCLC cell proliferation and cell cycle.
Fig. 4: FOS inhibits NSCLC cell migration and cell invasion.
Fig. 5: Knocking down FAK suppresses the inhibitory effect of FOS on NSCLC.
Fig. 6: FOS suppresses the proliferation of xenografted NSCLC cells.
Fig. 7: FOS inhibits the phosphorylation of multiple sites on FAK and blocks the AKT/JNK/c-Jun signaling.
Fig. 8: FOS suppresses NSCLC mainly by inhibiting Y925 phosphorylation of FAK.
Fig. 9: Mechanistic model showing the suppressive effect of FOS on NSCLC.

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Acknowledgements

This work was supported by grants from the 6th “ 333 High-level Talents Training Project ” of Jiangsu Province (Grant No. 2022-3-25-162), the Jiangsu Provincial Medical Key Discipline (Grant No. ZDXK202201), Original Exploration program for Suzhou Basic Research (Grant No. SSD2024036), the Scientific Research Project of Jiangsu Provincial Health Commission (Grant No. H2023115), and Suzhou Medical College-QiLu Medical Research Program of Soochow University (Grant No. 24QL200104).

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  1. These authors contributed equally: Ying Wang, Yu-na Shao, Chen-kang Ma

Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China

    Ying Wang, Yu-na Shao, Chen-kang Ma, Chen-ying Shu, Yi-hua Zhang, Di Lu, Hui-ling Zhang, Jian-jie Zhu, Yuan-yuan Zeng, Jian-jun Li & Ze-yi Liu

  2. Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou 215006, China

    Ying Wang, Yu-na Shao, Chen-ying Shu, Yi-hua Zhang & Zhao-wei Yan

  3. College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China

    Ying Wang, Yu-na Shao, Chen-ying Shu, Yi-hua Zhang & Zhao-wei Yan

  4. Institute of Respiratory Diseases, Soochow University, Suzhou 215006, China

    Chen-kang Ma, Di Lu, Hui-ling Zhang, Jian-jie Zhu, Yuan-yuan Zeng, Jian-jun Li & Ze-yi Liu

  5. Suzhou Key Laboratory for Respiratory Diseases, Suzhou 215006, China

    Ze-yi Liu

  6. Cancer Institute, Suzhou Medical College, Soochow University, Suzhou 215123, China

    Ze-yi Liu

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Contributions

YW and YNS edited the manuscript; CKM, CYS, and YHZ processed the data; DL, HLZ; JJZ, YYZ, and JJL supervised; ZWY and ZYL provided funding.

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Correspondence to Zhao-wei Yan or Ze-yi Liu.

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Wang, Y., Shao, Yn., Ma, Ck. et al. Antiemetic drug fosaprepitant exerts anti-tumor effects against NSCLC by targeting FAK to inhibit AKT and JNK/c-Jun pathways. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01645-0

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