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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2024 | Ovarian Cancer | Research

Targeting of focal adhesion kinase enhances the immunogenic cell death of PEGylated liposome doxorubicin to optimize therapeutic responses of immune checkpoint blockade

Authors: Baoyuan Zhang, Ning Li, Jiaming Gao, Yuxi Zhao, Jun Jiang, Shuang Xie, Cuiping Zhang, Qingyu Zhang, Leo Liu, Zaiqi Wang, Dongmei Ji, Lingying Wu, Ruibao Ren

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2024

Abstract

Backgrounds

Immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of an immunogenic niche. Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy.

Methods

Here, we used drug screening, in vitro and in vivo assays to filter out that doxorubicin and its liposomal form pegylated liposome doxorubicin (PLD) showed synergistic anti-tumor effects in combination with FAK inhibitor IN10018. We hypothesized that anti-tumor immunity and immunogenic cell death (ICD) may be involved in the treatment outcomes through the data analysis of our clinical trial testing the combination of IN10018 and PLD. We then performed cell-based assays and animal studies to detect whether FAK inhibition by IN10018 can boost the ICD of PLD/doxorubicin and further established syngeneic models to test the antitumor effect of triplet combination of PLD, IN10018, and ICB.

Results

We demonstrated that the combination of FAK inhibitor IN10018, and PLD/doxorubicin exerted effective antitumor activity. Notably, the doublet combination regimen exhibited response latency and long-lasting treatment effects clinically, outcomes frequently observed in immunotherapy. Our preclinical study confirmed that the 2-drug combination can maximize the ICD of cancer cells. This approach primed the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Finally, different animal studies confirmed that the antitumor effects of ICB can be significantly enhanced by this doublet regimen.

Conclusions

We confirmed that targeting FAK by IN10018 can enhance the ICD of PLD/doxorubicin, further benefiting the anti-tumor effect of ICB. The animal tests of the triplet regimen warrant further discovery in the real world.

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Title: Targeting of focal adhesion kinase enhances the immunogenic cell death of PEGylated liposome doxorubicin to optimize therapeutic responses of immune checkpoint blockade
Authors: Baoyuan Zhang
Ning Li
Jiaming Gao
Yuxi Zhao
Jun Jiang
Shuang Xie
Cuiping Zhang
Qingyu Zhang
Leo Liu
Zaiqi Wang
Dongmei Ji
Lingying Wu
Ruibao Ren
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Ovarian Cancer
Ovarian Cancer
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2024
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-024-02974-4

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

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Abstract

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